Tricyclic heterocycles as BET protein inhibitors

ABSTRACT

The present invention relates to tricyclic heterocycles of Formula (I), which are inhibitors of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and are useful in the treatment of diseases such as cancer.

TECHNICAL FIELD

The present invention relates to tricyclic heterocycles which areinhibitors of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and areuseful in the treatment of diseases such as cancer.

BACKGROUND

The genomes of eukaryotic organisms are highly organized within thenucleus of the cell. DNA is packaged into chromatin by wrapping around acore of histone proteins to form a nucleosome. These nucleosomes arefurther compacted by aggregation and folding to form a highly condensedchromatin structure. A range of different states of condensation arepossible, and the tightness of this structure varies during the cellcycle, being most compact during the process of cell division. Chromatinstructure plays a critical role in regulating gene transcription byregulating protein access to the DNA. The chromatin structure iscontrolled by a series of post translational modifications to histoneproteins, mainly within the tails of histones H3 and H4 that extendbeyond the core nucleosome structure. These reversible modificationsinclude acetylation, methylation, phosphorylation, ubiquitination andSUMOylation. These epigenetic marks are written and erased by specificenzymes that modify specific residues within the histone tail, therebyforming an epigenetic code. Other nuclear proteins bind to these marksand effect outputs specified by this information through the regulationof chromatin structure and gene transcription. Increasing evidence linksgenetic changes to genes encoding epigenetic modifiers and regulatorsleading to aberrant histone marks in diseases such as neurodegenerativedisorders, metabolic diseases, inflammation and cancer.

Histone acetylation is typically associated with the activation of genetranscription, as the modification weakens the interaction between theDNA and the histone proteins, permitting greater access to DNA by thetranscriptional machinery. Specific proteins bind to acetylated lysineresidues within histones to “read” the epigenetic code. A highlyconserved protein module called the bromodomain binds to acetylatedlysine residues on histone and other proteins. There are more than 60bromodomain-containing proteins in the human genome.

The BET (Bromodomain and Extra-Terminal) family of bromodomaincontaining proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-t)that share a conserved structural organization containing tandemN-terminal bromodomains capable of binding to acetylated lysine residuesof histones and other proteins. BRD2, BRD3 and BRD4 are ubiquitiouslyexpressed while BRDt is restricted to germ cells. BRD proteins playessential, but non-overlapping roles in regulating gene transcriptionand controlling cell growth. BET proteins are associated with largeprotein complexes including Mediator, PAFc and super elongation complexthat regulate many aspects of gene transcription. BRD2 and BRD4 proteinshave been shown to remain in complex with chromosomes during mitosis andare required to promote transcription of critical genes including cyclinD and c-Myc that initiate the cell cycle (Mochizuki J Biol. Chem. 2008283:9040-9048). BRD4 is essential for recruiting the proteintranslational elongation factor B complex to the promoters of induciblegenes resulting in the phosphorylation of RNA polymerase II andstimulating productive gene transcription and elongation (Jang et al.Mol. Cell 2005 19:523-534). In some instances, a kinase activity of BRD4may directly phosphorylate and activate RNA polymerase II (Devaiah etal. PNAS 2012 109:6927-6932). Cells lacking BRD4 show impairedprogression through cell cycle. BRD2 and BRD3 are reported to associatewith histones along actively transcribed genes and may be involved infacilitating transcriptional elongation (Leroy et al, Mol. Cell. 200830:51-60). In addition to acetylated histones, BET proteins have beenshown to bind selectively to acetylated transcription factors includingthe RelA subunit of NF-kB and GATA1 thereby directly regulating thetranscriptional activity of these proteins to control expression ofgenes involved in inflammation and hematopoietic differentiation (Huanget al, Mol. Cell. Biol. 2009 29:1375-1387; Lamonica Proc. Nat. Acad.Sci. 2011 108:E159-168).

A recurrent translocation involving NUT (nuclear protein in testes) withBRD3 or BRD4 to form a novel fusion oncogene, BRD-NUT, is found in ahighly malignant form of epithelial neoplasia (French et al, CancerResearch 2003 63:304-307; French et al, Journal of Clinical Oncology2004 22:4135-4139). Selective ablation of this oncogene restores normalcellular differentiation and reverses the tumorigenic phenotype(Filippakopoulos et al, Nature 2010 468:1068-1073). Genetic knockdown ofBRD2, BRD3 and BRD4 has been shown to impair the growth and viability ofa wide range of hematological and solid tumor cells (Zuber et al, Nature2011 478:524-528; Delmore et al, Cell 2011 146:904-917). Aside from arole in cancer, BET proteins regulate inflammatory responses tobacterial challenge, and a BRD2 hypomorph mouse model showeddramatically lower levels of inflammatory cytokines and protection fromobesity induced diabetes (Wang et al Biochem J. 2009 425:71-83; Belkinaet al. J. Immunol 2013). In addition, some viruses make use of these BETproteins to tether their genomes to the host cell chromatin, as part ofthe process of viral replication or use BET proteins to facilitate viralgene transcription and repression (You et al, Cell 2004 117:349-60; Zhuet al, Cell Reports 2012 2:807-816).

Accordingly, there is a need for compounds that modulate the activity ofthe BET family of proteins, including BRD2, BRD3, and BRD4, that can beused to treat BET protein-associated diseases such as cancer. Thecompounds of the invention help meet this need.

SUMMARY

The present invention provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein the variables areas defined below.

The present invention also provides a composition comprising a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, and atleast one pharmaceutically acceptable carrier.

The present invention also provides methods of treating cancer and otherdiseases comprising administering to a patient a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

The present invention also provides use of a compound of the Formula(I), or a pharmaceutically acceptable salt thereof, for use in therapy.

The present invention also provides a compound of the Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment of adisease referenced herein.

The details of one or more embodiments are set forth in the descriptionbelow. Other features, objects, and advantages will be apparent from thedescription and from the claims.

DETAILED DESCRIPTION

For the terms “e.g.” and “such as,” and grammatical equivalents thereof,the phrase “and without limitation” is understood to follow unlessexplicitly stated otherwise.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

As used herein, the term “about” means “approximately” (e.g., plus orminus approximately 10% of the indicated value).

I. Compounds

The present disclosure relates, inter alia, to a compound of a BETprotein-inhibiting compound of Formula (I):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   represents a single bond or a double bond;    -   L is CR⁹R^(9a), O, S, SO, or SO₂;    -   X is N or NR⁵;    -   Y is N, CR⁶, C(═O), or C(═S);    -   provided X is not NR⁵ when Y is N;    -   Cy¹ is selected from phenyl and a 5-6 membered heteroaryl group        comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N,        O and S, wherein said phenyl and 5-6 membered heteroaryl of Cy¹        are optionally substituted with 1, 2, 3, or 4 groups        independently selected from R¹¹;

R¹ and R² are independently selected from H, halo, CN, OH, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a1), SR^(a1),C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1),OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)NR^(c1)R^(d1), NR^(c1)C(═O)OR^(a1), S(═O)R^(b1),S(═O)NR^(c1)R^(d1), S(═O)₂R^(b1), NR^(c1)S(═O)₂R^(b1) andS(═O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹ and R² are optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a1), SR^(a1), C(═O)R^(b1),C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1), NR^(c1)C(═O)NR^(c1)R^(d1),NR^(c1)C(═O)OR^(a1), S(═O)R^(b1), S(═O)NR^(c1)R^(d1), S(═O)₂R^(b1),NR^(c1)S(═O)₂R^(b1) and S(═O)₂NR^(c1)R^(d1);

-   -   provided R¹ and R² are other than Cl, Br, I, CN, and OH when L        is O or S;    -   alternatively, R¹ and R² together with the carbon atom to which        they are attached form a C₃₋₇ cycloalkyl group, wherein said        cycloalkyl group is optionally substituted with 1, 2, 3, or 4        groups independently selected from R²⁰;    -   Cy³ is selected from phenyl, C₃₋₇ cycloalkyl, a 5-10 membered        heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms        selected from N, O and S, and a 4-10 membered heterocycloalkyl        group comprising carbon and 1, 2, or 3 heteroatoms selected from        N, O and S, wherein said phenyl, C₃₋₇ cycloalkyl, 5-10 membered        heteroaryl, and 4-10 membered heterocycloalkyl of Cy³ are        optionally substituted with 1, 2, 3, or 4 groups independently        selected from R¹³, wherein a ring-forming nitrogen atom of said        5-10 membered heteroaryl group or a ring-forming nitrogen atom        of said 4-10 membered heterocycloalkyl group is optionally        oxidized;    -   R⁴ is H or C₁₋₆ alkyl;    -   R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, phenyl, C₃₋₇ cycloalkyl, a 5-6 membered        heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms        selected from N, O and S, and a 4-7 membered heterocycloalkyl        group comprising carbon and 1, 2, or 3 heteroatoms selected from        N, O and S, wherein said C₁₋₆ alkyl, phenyl, C₃₋₇ cycloalkyl,        5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R⁵        are optionally substituted by 1, 2, 3, or 4 groups independently        selected from R¹⁵;    -   R⁶ is selected from H, halo, CN, OH, OR^(a6), SR^(a6),        C(═O)R^(b6), C(═O)NR^(c6)R^(d6), C(═O)OR^(a6), OC(═O)R^(c6),        OC(═O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(═O)R^(b6),        NR^(c6)C(═O)NR^(c6)R^(d6), NR^(c6)C(═O)OR^(a6), S(═O)R^(b6),        S(═O)NR^(c6)R^(d6), S(═O)₂R^(b6), NR^(c6)S(═O)₂R^(b6),        S(═O)₂NR^(c6)R^(d6), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and        C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl of R⁶ are each optionally substituted by 1, 2, 3, or 4        groups independently selected from R¹⁶;    -   alternatively, R⁶ is selected from C₆₋₁₀ aryl, C₃₋₇ cycloalkyl,        a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3        or 4 heteroatoms selected from N, O and S, and a 4-7 membered        heterocycloalkyl group comprising carbon and 1, 2, or 3        heteroatoms selected from N, O and S, wherein said C₆₋₁₀ aryl,        C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered        heterocycloalkyl of R⁶ are each optionally substituted by 1, 2,        3, or 4 groups independently selected from R²⁰;    -   R⁷ is selected from H, halo, CN, OR^(a), NR^(c)R^(d), SR^(b),        CONR^(c)R^(d), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl        group comprising carbon and 1, 2, 3 or 4 heteroatoms selected        from N, O and S, and a 4-7 membered heterocycloalkyl group        comprising carbon and 1, 2, or 3 heteroatoms selected from N, O        and S, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl group, and 4-7        membered heterocycloalkyl group of R⁷ are optionally substituted        with 1, 2, or 3 groups independently selected from R¹⁷;    -   R⁸ is selected from H, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl,        C₁₋₃ haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), and        CONR^(c)R^(d), wherein said C₁₋₃ alkyl, C₂₋₃ alkenyl, and C₂₋₃        alkynyl of R⁸ are optionally substituted with 1, 2, or 3 groups        independently selected from R¹¹;    -   R⁹ and R^(9a) are independently selected from H, C₁₋₃ alkyl,        C₁₋₃ haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), and        CONR^(c)R^(d);    -   R¹¹ is independently at each occurrence selected from H, C₁₋₃        alkyl, C₁₋₃ haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b),        and CONR^(c)R^(d);    -   R¹³ is independently at each occurrence selected from H, halo,        CN, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        OR^(a3), SR^(a3), C(═O)R^(b3), C(═O)NR^(c3)R^(d3), C(═O)OR^(a3),        OC(═O)R^(b3), OC(═O)NR^(c3)R^(d3), NR^(c3)R^(d3),        NR^(c3)C(═O)R^(b3), NR^(c3)C(═O)NR^(c3)R^(d3),        NR^(c3)C(═O)OR^(a3), S(═O)R^(b3), S(═O)NR^(c3)R^(d3),        S(═O)₂R^(b3), NR^(c3)S(═O)₂R^(b3) and S(═O)₂NR^(c3)R^(d3),        wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R¹³        are optionally substituted with 1, 2, or 3 groups independently        selected from halo, CN, OH, OR^(a3), SR^(a3), C(═O)R^(b3),        C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3),        OC(═O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3),        NR^(c3)C(═O)NR^(c3)R^(d3), NR^(c3)C(═O)OR^(a3), S(═O)R^(b3),        S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3), NR^(c3)S(═O)₂R^(b3) and        S(═O)₂NR^(c3)R^(d3);    -   R¹⁵ is independently at each occurrence selected from H, halo,        CN, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(c5), C(═O)OR^(a5),        OC(═O)R^(b5), OC(═O)NR^(c5)R^(c5), NR^(c5)R^(c5),        NR^(c5)C(═O)R^(b5), NR^(c5)C(═O)NR^(c5)R^(c5),        NR^(c5)C(═O)OR^(a5), S(═O)R^(b5), S(═O)NR^(c5)R^(c5),        S(═O)₂R^(b5), NR^(c5)S(═O)₂R^(b5) and S(═O)₂NR^(c5)R^(d5),        wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R¹⁵        are optionally substituted with 1, 2, or 3 groups independently        selected from halo, CN, OH, OR^(a5), SR^(a5), C(═O)R^(b5),        C(═O)NR^(c5)R^(c5), C(═O)OR^(a5), OC(═O)R^(b5),        OC(═O)NR^(c5)R^(c5), NR^(c5)R^(c5), NR^(c5)C(═O)R^(b5),        NR^(c5)C(═O)NR^(c5)R^(c5), NR^(c5)C(═O)OR^(a5), S(═O)R^(b5),        S(═O)NR^(c5)R^(c5), S(═O)₂R^(b5), NR^(c5)S(═O)₂R^(b5) and        S(═O)₂NR^(c5)R^(d5);    -   R¹⁶ is independently at each occurrence selected from halo, CN,        OH, OR^(a6), SR^(a6), C(═O)R^(b6), C(═O)NR^(c6)R^(d6),        C(═O)OR^(a6), OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6), NR^(c6)R^(d6),        NR^(c6)C(═O)R^(b6), NR^(c6)C(═O)NR^(c6)R^(d6),        NR^(c6)C(═O)OR^(a6), S(═O)R^(b6), S(═O)NR^(c6)R^(d6),        S(═O)₂R^(b6), NR^(c6)S(═O)₂R^(b6), S(═O)₂NR^(c6)R^(d6), C₆₋₁₀        aryl, C₃₋₇ cycloalkyl, a 5-10 membered heteroaryl group        comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N,        O and S, and a 4-7 membered heterocycloalkyl group comprising        carbon and 1, 2, or 3 heteroatoms selected from N, O and S,        wherein said C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered        heteroaryl, and 4-7 membered heterocycloalkyl of R¹⁶ are each        optionally substituted by 1, 2, 3, or 4 groups independently        selected R²⁰;    -   R¹⁷ and R¹⁸ are independently at each occurrence selected from        halo, CN, OR^(a), NR^(c)R^(d), SR^(b), and CONR^(c)R^(d);    -   R^(a), R^(c), and R^(d) are independently at each occurrence        selected from H and C₁₋₆ alkyl;    -   R^(b) is at each occurrence C₁₋₆ alkyl;    -   R^(a1), R^(b1), R^(c1) and R^(d1) are independently at each        occurrence selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl forming R^(a1), R^(b1), R^(c1) and        R^(d1) are each optionally substituted with 1, 2, or 3        substituents independently selected from R²⁰;    -   R^(a3), R^(b3), R^(a1) and R^(d3) are independently at each        occurrence selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl forming R^(a3), R^(b3), R^(a1) and        R^(d3) are each optionally substituted with 1, 2, or 3        substituents independently selected from halo, CN, OH, OR^(a4),        SR^(a4), C(═O)R^(b4), C(═O)NR^(c4)R^(d4), C(═O)OR^(a4),        OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4),        NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)NR^(c4)R^(d4),        NR^(c4)C(═O)OR^(a4), S(═O)R^(b4), S(═O)NR^(c4)R^(d4),        S(═O)₂R^(b4), NR^(c4)S(═O)₂R^(b4) and S(═O)₂NR^(c4)R^(d4);    -   R^(a4), R^(b4), R^(c4) and R^(d4) are independently at each        occurrence selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl forming R^(a4), R^(b4), R^(c4) and        R^(d4) are each optionally substituted with 1, 2, or 3        substituents independently selected from R²⁰;    -   R^(a5), R^(b5), R^(c5) and R^(d5) are independently at each        occurrence selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl forming R^(a5), R^(b5), R^(c5) and        R^(d5) are each optionally substituted with 1, 2, or 3        substituents independently selected from R²⁰;    -   R^(a6), R^(c6) and R^(d6) are independently at each occurrence        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl        group comprising carbon and 1, 2, 3 or 4 heteroatoms selected        from N, O and S, and a 4-7 membered heterocycloalkyl group        comprising carbon and 1, 2, or 3 heteroatoms selected from N, O        and S, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl        group, and 4-7 membered heterocycloalkyl group forming R^(a6),        R^(c6) and R^(d6) are each optionally substituted with 1, 2, or        3 substituents independently selected from R²⁰;    -   alternatively, R^(c6) and R^(d6) together with the nitrogen atom        to which they are attached may be combined to form a 4-7        membered heterocycloalkyl group comprising carbon, nitrogen, and        0, 1, or 2 additional heteroatoms selected from N, O and S,        wherein said 4-7 membered heterocycloalkyl group is optionally        substituted with 1, 2, or 3 substituents independently selected        from R²⁰;    -   R^(b6) is independently at each occurrence selected from C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₇        cycloalkyl, a 5-6 membered heteroaryl group comprising carbon        and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7        membered heterocycloalkyl group comprising carbon and 1, 2, or 3        heteroatoms selected from N, O and S, wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₇        cycloalkyl, 5-6 membered heteroaryl group, and 4-7 membered        heterocycloalkyl group are each optionally substituted with 1,        2, or 3 substituents independently selected from R²⁰; and    -   R²⁰ is at each occurrence independently selected from H, halo,        OH, CN, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄        alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ halo alkyl, C₁₋₄        haloalkoxy, C₁₋₄ alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)O—, C₁₋₄        alkyl-OC(═O)—, HOC(═O)—, H₂NC(═O)—, C₁₋₄ alkyl-NHC(═O)—, di(C₁₋₄        alkyl)NC(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄ alkyl-S(═O)—,        H₂NS(═O)—, C₁₋₄ alkyl-NHS(═O)—, di(C₁₋₄ alkyl)NS(═O)—, C₁₋₄        alkyl-S(═O)₂—, C₁₋₄ alkyl-S(═O)₂NH—, H₂NS(═O)₂—, C₁₋₄        alkyl-NHS(═O)₂—, and di(C₁₋₄ alkyl)NS(═O)₂—.

In some embodiments, L is O.

In some embodiments, L is S.

In some embodiments, L is CR⁹CR^(9a).

In some embodiments, L is CH₂.

In some embodiments, X is N.

In some embodiments, X is NR⁵.

In some embodiments, Y is CR⁶.

In some embodiments, Y is C(═O).

In some embodiments, X

Y is N═N.

In some embodiments, Cy¹ is isoxazolyl substituted with 1 or 2 groupsindependently selected from R¹¹.

In some embodiments, Cy¹ is pyrazolyl substituted with 1 or 2 groupsindependently selected from R¹¹.

In some embodiments, R¹ is selected from H, methyl, —C(═O)OCH₂CH₃,—C(═O)N(H)CH₂CH₃, —C(═O)N(H)CH₂CH₂OH, and —C(═O)N(CH₃)₂.

In some embodiments, R¹ is H.

In some embodiments, R¹ is methyl.

In some embodiments, R² is H.

In some embodiments, Cy³ is selected from phenyl, pyridinyl,oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl andtetrahydrofuranyl, wherein said phenyl, pyridinyl, oxidopyridinyl,thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl isoptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R¹³.

In some embodiments, Cy³ is phenyl optionally substituted with 1, 2, 3,or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is pyridinyl optionally substituted with 1, 2,3, or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is oxidopyridinyl optionally substituted with1, 2, 3, or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is thiazolyl optionally substituted with 1, 2,3, or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is cyclohexyl optionally substituted with 1, 2,3, or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is dihydrobenzofuranyl optionally substitutedwith 1, 2, 3, or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is tetrahydrofuranyl optionally substitutedwith 1, 2, 3, or 4 groups independently selected from R¹³.

In some embodiments, R⁵ is methyl.

In some embodiments, R⁵ is H.

In some embodiments, R⁶ is H, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, or C₁₋₆ haloalkyl.

In some embodiments, R⁶ is H.

In some embodiments, R⁶ is methoxy.

In some embodiments, R⁷ is selected from H, halo, C₁₋₄ alkyl, and CN.

In some embodiments, R⁷ is selected from H, Br, F, methyl, and CN.

In some embodiments, R⁷ is H.

In some embodiments, R⁷ is Br.

In some embodiments, R⁷ is F.

In some embodiments, R⁷ is methyl.

In some embodiments, R⁷ is CN.

In some embodiments, R⁸ is selected from H, halo, C₁₋₄ alkyl, and CN.

In some embodiments, R⁸ is H.

In some embodiments, the compounds of the invention have Formula (IIa),(IIb), or (IIc):

In some embodiments, the compounds of the invention have Formula (IIIa),(IIIb), or (IIIc):

In some embodiments:

-   -   L is O or S;    -   Y is N, CR⁶, or C(═O);    -   Cy¹ is a 5-6 membered heteroaryl group comprising carbon and 1,        2, 3 or 4 heteroatoms selected from N, O and S, wherein said 5-6        membered heteroaryl of Cy¹ is optionally substituted with 1, 2,        3, or 4 groups independently selected from R¹¹;    -   R¹ is selected from H, F, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ haloalkyl, OR^(a1), C(═O)R^(b1),        C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), NR^(c1)R^(d1), and        NR^(c1)C(═O)R^(b1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and        C₂₋₆ alkynyl of R¹ is optionally substituted with 1, 2, or 3        groups independently selected from halo, CN, OH, OR^(a1),        C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), NR^(c1)R^(d1),        and NR^(c1)C(═O)R^(b1); provided R¹ is not OH;    -   R⁷ is selected from H, halo, CN, OR^(a), C₁₋₆ alkyl, C₁₋₆        haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl        group comprising carbon and 1, 2, 3 or 4 heteroatoms selected        from N, O and S, and a 4-7 membered heterocycloalkyl group        comprising carbon and 1, 2, or 3 heteroatoms selected from N, O        and S, wherein said C₁₋₆ alkyl, phenyl, C₃₋₇ cycloalkyl, 5-6        membered heteroaryl group, and 4-7 membered heterocycloalkyl        group of R⁷ are optionally substituted with 1, 2, or 3 groups        independently selected from R¹⁷;    -   R⁸ is selected from H and C₁₋₃ alkyl; and    -   R^(a1), R^(b1), R^(c1) and R^(d1) are independently at each        occurrence selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments:

-   -   L is O;    -   Y is N, CR⁶, or C(═O);    -   Cy¹ is a 5-membered heteroaryl group comprising carbon and 1, 2,        3 or 4 heteroatoms selected from N, O and S, wherein said        5-membered heteroaryl of Cy¹ is optionally substituted with 1,        2, 3, or 4 groups independently selected from R¹¹;    -   R¹ and R² are both H;    -   Cy³ is selected from phenyl and a 5-6 membered heteroaryl group        comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N,        O and S, wherein said phenyl and 5-6 membered heteroaryl of Cy³        are optionally substituted with 1, 2, 3, or 4 groups        independently selected from R¹³, wherein a ring-forming nitrogen        atom of said 5-6 membered heteroaryl group;    -   R⁴ is H;    -   R⁵ is selected from H and C₁₋₆ alkyl;    -   R⁶ is selected from H, OR^(a6);    -   R⁷ is selected from H and halo; and    -   R⁸ is H.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a substituent. It is to beunderstood that substitution at a given atom is limited by valency.Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. In someembodiments, the alkyl group contains from 1 to 6 carbon atoms or from 1to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.

As used herein, the term “C_(n-m) alkoxy”, employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy).In some embodiments, the alkyl group has 1 to 3 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. In someembodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms.Example alkenyl groups include, but are not limited to, ethenyl,n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6 or 2 to 4 carbon atoms.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “di-C_(n-m)-alkylamino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “aryl”, employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or4 fused rings) aromatic hydrocarbon, such as, but not limited to,phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and thelike. In some embodiments, aryl is C₆₋₁₀ aryl. In some embodiments, thearyl group is a naphthalene ring or phenyl ring. In some embodiments,the aryl group is phenyl.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “cycloalkyl”, employed alone or in combinationwith other terms, refers to a non-aromatic cyclic hydrocarbon moiety,which may optionally contain one or more alkenylene groups as part ofthe ring structure. Cycloalkyl groups can include mono- or polycyclic(e.g., having 2, 3 or 4 fused rings) ring systems. Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo derivatives of cyclopentane, cyclopentene,cyclohexane, and the like. One or more ring-forming carbon atoms of acycloalkyl group can be oxidized to form carbonyl linkages. In someembodiments, cycloalkyl is C₃₋₇ cycloalkyl, which is monocyclic orbicyclic. Examplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, andthe like. In some embodiments, the cycloalkyl group is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. An example haloalkoxy group isOCF₃. An additional example haloalkoxy group is OCHF₂. In someembodiments, the haloalkoxy group is fluorinated only. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “halo” refers to a halogen atom selected fromF, Cl, I or Br. In some embodiments, “halo” refers to a halogen atomselected from F, Cl, or Br. In some embodiments, exemplary halo groupsare F.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the haloalkyl group isfluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments,the haloalkyl group is trifluoromethyl. In some embodiments, the alkylgroup has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “heteroaryl”, employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2,3 or 4 fused rings) aromatic hydrocarbon moiety, having one or moreheteroatom ring members selected from nitrogen, sulfur and oxygen. Insome embodiments, heteroaryl is 5- to 10-membered C₁₋₉ heteroaryl, whichis monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ringmembers independently selected from nitrogen, sulfur and oxygen. Whenthe heteroaryl group contains more than one heteroatom ring member, theheteroatoms may be the same or different. The nitrogen atoms in thering(s) of the heteroaryl group can be oxidized to form N-oxides.Example heteroaryl groups include, but are not limited to, pyridine,pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole,isoxazole, thiazole, isothiazole, imidazole, furan, thiophene, triazole,tetrazole, thiadiazole, quinoline, isoquinoline, indole, benzothiophene,benzofuran, benzisoxazole, imidazo[1,2-b]thiazole, purine, triazine orthe like.

A 5-membered heteroaryl is a heteroaryl group having five ring atomscomprising carbon and one or more (e.g., 1, 2, or 3) ring atomsindependently selected from N, O, and S. Exemplary five-membered ringheteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl,oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

A 6-membered heteroaryl is a heteroaryl group having six ring atomswherein one or more (e.g., 1, 2, or 3) ring atoms are nitrogen.Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,pyrimidinyl, triazinyl and pyridazinyl.

As used herein, the term “heterocycloalkyl”, employed alone or incombination with other terms, refers to non-aromatic ring system, whichmay optionally contain one or more alkenylene or alkynylene groups aspart of the ring structure, and which has at least one heteroatom ringmember independently selected from nitrogen, sulfur and oxygen. When theheterocycloalkyl group contains more than one heteroatom, theheteroatoms may be the same or different. Heterocycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ringsystems, including spiro systems. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the non-aromatic ring, forexample, 1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran and the like.The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkylgroup can be oxidized to form a carbonyl, or sulfonyl group (or otheroxidized linkage) or a nitrogen atom can be quaternized. In someembodiments, heterocycloalkyl is 5- to 10-membered C₂₋₉heterocycloalkyl, which is monocyclic or bicyclic and which has 1, 2, 3,or 4 heteroatom ring members independently selected from nitrogen,sulfur and oxygen. Examples of heterocycloalkyl groups include1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran, azetidine, azepane,pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, andpyran.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereoisomers, are intended unless otherwise indicated. Compounds ofthe present invention that contain asymmetrically substituted carbonatoms can be isolated in optically active or racemic forms. Methods onhow to prepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

When the compounds of the invention contain a chiral center, thecompounds can be any of the possible stereoisomers. In compounds with asingle chiral center, the stereochemistry of the chiral center can be(R) or (S). In compounds with two chiral centers, the stereochemistry ofthe chiral centers can each be independently (R) or (S) so theconfiguration of the chiral centers can be (R) and (R), (R) and (S); (S)and (R), or (S) and (S). In compounds with three chiral centers, thestereochemistry each of the three chiral centers can each beindependently (R) or (S) so the configuration of the chiral centers canbe (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and(S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S)and (S).

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone enol pairs, amide-imidic acidpairs, lactam lactim pairs, amide-imidic acid pairs, enamine iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified (e.g., in the case of purine rings,unless otherwise indicated, when the compound name or structure has the9H tautomer, it is understood that the 7H tautomer is also encompassed).

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in a compound of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (MeCN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17^(th) Ed., (Mack PublishingCompany, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977,66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (Wiley, 2002). In some embodiments, thecompounds described herein include the N-oxide forms.

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); br (broad); Cbz (carboxybenzyl); calc. (calculated);d (doublet); dd (doublet of doublets); DCM (dichloromethane); DIAD(N,N′-diisopropyl azidodicarboxylate); DIPEA(N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); Et (ethyl);EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography mass spectrometry); m (multiplet); M (molar); mCPBA(3-chloroperoxybenzoic acid); MgSO₄ (magnesium sulfate); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); NaHCO₃ (sodium bicarbonate); NaOH (sodiumhydroxide); Na₂SO₄ (sodium sulfate); NH₄Cl (ammonium chloride); NH₄OH(ammonium hydroxide); nM (nanomolar); NMR (nuclear magnetic resonancespectroscopy); OTf (trifluoromethanesulfonate); Pd (palladium); Ph(phenyl); pM (picomolar); POCl₃ (phosphoryl chloride); RP-HPLC (reversephase high performance liquid chromatography); s (singlet); t (tripletor tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt(triplet of triplets); t-Bu (tert-butyl); TFA (trifluoroacetic acid);THF (tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM(micromolar); wt % (weight percent).

II. Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in P. G. M. Wuts and T. W.Greene, Protective Groups in Organic Synthesis, 4^(th) Ed., Wiley &Sons, Inc., New York (2006), which is incorporated herein by referencein its entirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) (“Preparative LC-MSPurification: Improved Compound Specific Method Optimization” Karl F.Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004,6(6), 874-883, which is incorporated herein by reference in itsentirety) and normal phase silica chromatography.

Compounds of Formula (I) can be formed as shown in Scheme I. The phenols(L=O) or thiols (L=S) (i) can be nitrated using standard conditions(HNO₃/H₂SO₄) and esterified using standard conditions (SOCl₂/MeOH or(COCl)₂/MeOH) to give (iii). Phenol (iii) can be protected (e.g.,protecting group P=benzyl) to give (iv). The halo group of (iv) can becoupled to M-Cy¹, where M is a boronic acid, boronic ester or anappropriately substituted metal (e.g., Cy¹-M is Cy¹-B(OH)₂, Cy¹-Sn(Bu)₄,or Zn—Cy¹), under standard Suzuki conditions or standard Stilleconditions (e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base) or standard Negishi conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give compounds (v).Alternatively, M-Cy¹ can be an amine containing heterocycle (where M isH and is attached to the amine nitrogen of the heterocycle Cy¹) withcoupling to compound (iv) being performed by heating with a base orunder Buchwald conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., an alkoxide base)) to give compounds (v). The nitro group of (v)can be reduced under standard conditions (e.g., Pd, Fe or Zn) to givethe amino compound which can be deprotected if necessary to give (vi).Aniline (vi) can be alkylated using standard alkylating conditions withCy³COC(R¹R²)—X (ii) (X=leaving group, such as halo (Br, Cl, or I) ormesylate) or Mitsunobu conditions (e.g., Cy³COC(R¹R²)—X (ii) (X═OH),DEAD, Ph₃P) to afford ether or thioether derivatives (vii). The imine ofcompound (vii) can be reduced (e.g., hydrogenation with palladium) togive compound (viii) (R⁴═H) or treated with a Grignard reagent offormula R⁴—MgX¹ (X¹=halo) to give (viii). Treatment of compound (viii)with sodium nitrite can give compound (ix). Reduction of nitroso (ix)(e.g., sodium dithionite, zinc with acetic acid, or zinc with saturatedaqueous ammonium chloride) gives the hydrazine which can cyclize (insitu or with heat) with the adjacent ester to give compounds of Formula(I) (x). Compound (x) can be alkylated (e.g., alkyl halide and a base,such as triethylamine, NaH or Na₂CO₃; or under Mitsunobu conditions) toafford the N-substituted derivatives of Formula (I) (xi) orO-substituted derivatives of Formula (I) (xii) (R⁶═OR^(a6)).

Compounds of Formula (I) can be formed as shown in Scheme II. Ester (i)(compound (viii) from Scheme 1) can be reduced under standard conditions(e.g., LAH) to give alcohol (ii). Treatment of (ii) with sodium nitritefollowed by reduction (e.g., LAH) can give hydrazine (iii). Oxidation ofalcohol (iii) to the aldehyde (e.g., Swern oxidation) and intramolecularcyclization with the hydrazine gives derivatives of Formula (I) (iv).Alternatively, compound (ii) can be oxidized (e.g., Swern oxidation) togive aldehyde (v). Aldehyde (v) may then be reacted with a Grignardreagent of formula R⁶—MgX¹ (X¹=halo) to give alcohol (vi). Treatment of(vi) with sodium nitrite followed by reduction (e.g., LAH) can givehydrazine (vii). Oxidation of alcohol (vii) to the ketone (e.g., Swernoxidation) and intramolecular cyclization with the hydrazine givesderivatives of Formula (I) (viii).

Compounds of Formula (I) can be formed as shown in Scheme III. Compounds(i) can be halogenated with N-chlorosuccinimide, N-bromosuccinimide orN-iodosuccinimide to give halide (ii) where X═Cl, Br or I. The halogroup of (ii) can be coupled to M-R⁷, where M is a boronic acid, boronicester or an appropriately substituted metal (e.g., R⁷-M is R⁷—B(OH)₂,R⁷—Sn(Bu)₄, or Zn—R⁷), under standard Suzuki conditions or standardStille conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., abicarbonate or carbonate base) or standard Negishi conditions (e.g., inthe presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative ofFormula I (iii). Alternatively, M-R⁷ can be an amine containingheterocycle (where M is H and is attached to the amine nitrogen of theheterocycle R⁷) with coupling to compound (ii) being performed byheating with a base or under Buchwald conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to give a derivative of Formula (I) (iii).

Compounds of Formula (I) can be formed as shown in Scheme IV. Thephenols (L=O) or thiols (L=S) (i) can be alkylated using standardalkylating conditions with Cy³COC(R¹R²)—X (ii) (X=leaving group, such ashalo (Br, Cl, or I) or mesylate) or Mitsunobu conditions (e.g.,Cy³COC(R¹R²)—X (ii) (X═OH), DEAD, Ph₃P) to afford ether or thioetherderivatives (iii). Cyclization in situ or upon heating can afford imine(iv) which upon treatment with a Grignard reagent of formula R⁴—MgX¹(X¹=halo) and reduction of the nitro group (e.g., H₂ Pd/C or Fe) cangive an amine (v) or the Grignard treatment could be skipped to giveamine (v) (R⁴═H). Compounds (v) can be halogenated withN-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide followed bytreatment with sodium nitrite to give tricyclic halide (vi) where X═Cl,Br or I. The halo group of (vi) can be coupled to M-Cy¹, where M is aboronic acid, boronic ester or an appropriately substituted metal (e.g.,Cy¹-M is Cy¹-B(OH)₂, Cy¹-Sn(Bu)₄, or Zn—Cy¹), under standard Suzukiconditions or standard Stille conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., a bicarbonate or carbonate base) or standard Negishiconditions (e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative ofFormula (I) (vii). Alternatively, M-Cy¹ can be an amine containingheterocycle (where M is H and is attached to the amine nitrogen of theheterocycle Cy¹) with coupling to compound (vi) being performed byheating with a base or under Buchwald conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to give a derivative of Formula (I) (vii).

Compounds of Formula (I) can be formed as shown in Scheme V. The phenols(L=O) or thiols (L=S) (i) can be alkylated using standard alkylatingconditions with Cy³COC(R¹R²)—X (ii) (X=leaving group, such as halo (Br,Cl, or I) or mesylate) or Mitsunobu conditions (e.g., Cy³COC(R¹R²)—X(ii) (X═OH), DEAD, Ph₃P) to afford ether or thioether derivatives (iii)after displacement of the fluorine with an appropriately protected amine(NH₂P where P is a protecting group). Reduction of the nitro group of(iii) under standard conditions (e.g., Fe or Zn) can give the aminocompound which can cyclize in situ or upon heating to afford an iminewhich upon treatment with a Grignard reagent of formula R⁴—MgX¹ (X¹halo) can give amine (iv) or the imine can just be reduced with hydrogenover Pd/C to give amine (iv) where R⁴═H. Compounds (iv) can behalogenated with N-chlorosuccinimide, N-bromosuccinimide orN-iodosuccinimide to give tricyclic halide (v) where X═Cl, Br or Ifollowed by reaction to form the triazole with sodium nitrite. The halogroup of (v) can be coupled to M-Cy¹, where M is a boronic acid, boronicester or an appropriately substituted metal (e.g., Cy¹-M is Cy¹-B(OH)₂,Cy¹-Sn(Bu)₄, or Zn—Cy¹), under standard Suzuki conditions or standardStille conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., abicarbonate or carbonate base) or standard Negishi conditions (e.g., inthe presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative ofFormula (I) (vi). Alternatively, M-Cy¹ can be an amine containingheterocycle (where M is H and is attached to the amine nitrogen of theheterocycle Cy¹) with coupling to compound (v) being performed byheating with a base or under Buchwald conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to give a derivative of Formula (I) (vi).

Compounds of Formula (I) can be formed as shown in Scheme VI. Thephenols (L=O) or thiols (L=S) (i) can be nitrated using standardconditions (HNO₃/H₂SO₄) and selectively reduced with tin chloride togive the aniline nitro compound which can be alkylated using standardalkylating conditions with Cy³COC(R¹R²)—X (ii) (X=leaving group, such ashalo (Br, Cl, or I) or mesylate) or Mitsunobu conditions (e.g.,Cy³COC(R¹R²)—X (ii) (X═OH), DEAD, Ph₃P) to afford ether derivatives(iii). Cyclization in situ or upon heating can afford aminol (iv).Reduction of the nitro compound (iv) with iron can give, after in situdehydration, the aniline (v). The halo group of (v) can be coupled toM-Cy¹, where M is a boronic acid, boronic ester or an appropriatelysubstituted metal (e.g., Cy¹-M is Cy¹-B(OH)₂, Cy¹-Sn(Bu)₄, or Zn—Cy¹),under standard Suzuki conditions or standard Stille conditions (e.g., inthe presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base) or standard Negishi conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give compounds (vi).Alternatively, M-Cy¹ can be an amine containing heterocycle (where M isH and is attached to the amine nitrogen of the heterocycle Cy¹) withcoupling to compound (v) being performed by heating with a base or underBuchwald conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., analkoxide base)) to give compounds (vi). Reduction of imine (vi) (e.g.,sodium borohydride or Pd/H₂) followed by treatment with sodium nitritecan give derivatives of Formula (I) (vii).

Halo-ketone intermediates (ii) from Schemes I, IV, V, and VI can besynthesized as shown in Scheme VII. The carboxylic acid (i) can beactivated with a coupling agent (e.g., HBTU, HATU or EDC) and thenreacted with N, O-dimethylhydroxylamine to give aN-methoxy-N-methylcarboxamide derivative (ii). Amide (ii) may then bereacted with a Grignard reagent of formula R¹R²—CH—MgX¹ (X¹=halo) togive a ketone (iii) which can be halogenated with Br₂ or NXS (X═Br, Clor I) to give halo-ketone (iv). The halo-ketone (iv) can be transformedusing similar methods as shown in Schemes I, IV, V, and VI to affordcompounds of Formula (I).

Compounds of Formula (I) can be formed as shown in Scheme VIII. The halogroup of quinoline (i) can be coupled to M-Cy³, where M is a boronicacid, boronic ester or an appropriately substituted metal (e.g., Cy³-Mis Cy³-B(OH)₂, Cy³-Sn(Bu)₄, or Zn—Cy³), under standard Suzuki conditionsor standard Stille conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., a bicarbonate or carbonate base) or standard Negishi conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give compounds (ii).Reduction of quinoline (ii) (e.g., Hantzsch ester/diphenyl hydrogenphosphate or borane-pyridine complex/acetic acid) can givetetrahydroquinoline (iii). Treatment of the aniline of (iii) with sodiumnitrite can give nitroso compound (iv). Reduction of nitroso (iv) (e.g.,sodium dithionite, zinc with acetic acid, or zinc with saturated aqueousammonium chloride) gives the hydrazine which can cyclize (in situ orwith heat) with the adjacent ester to give tricyclic compounds (v).Compounds (v) can be halogenated with N-chlorosuccinimide,N-bromosuccinimide or N-iodosuccinimide to give halide (vi) where X═Cl,Br or I. The halo group of (vi) can be coupled to M-Cy¹, where M is aboronic acid, boronic ester or an appropriately substituted metal (e.g.,Cy¹-M is Cy¹-B(OH)₂, Cy¹-Sn(Bu)₄, or Zn—Cy¹), under standard Suzukiconditions or standard Stille conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., a bicarbonate or carbonate base) or standard Negishiconditions (e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative ofFormula (I) (vii). Alternatively, M-Cy¹ can be an amine containingheterocycle (where M is H and is attached to the amine nitrogen of theheterocycle Cy¹) with coupling to compound (vi) being performed byheating with a base or under Buchwald conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to give a derivative of Formula (I) (vii). Compound (vii) can bealkylated (e.g., alkyl halide and a base, such as triethylamine, NaH orNa₂CO₃; or under Mitsunobu conditions) to afford the N-substitutedderivatives of Formula (I) (viii) or O-substituted derivatives ofFormula (I) (ix) (R⁶═OR^(6B)).

Compounds of Formula (I) can be formed as shown in Scheme IX. Aniline(i) can be reacted with aldehyde of formula —OHCC(R¹)═CHCy³ (ii), togive quinoline derivatives (iii). Ester (iii) can then be converted tocompounds of Formula (I) by similar methods for ester (ii) shown inScheme VIII.

Compounds of Formula (I) can be formed as shown in Scheme X. The sulfide(i) can be reacted with an oxidant, such as mCPBA or H₂O₂ or dioxirane,to give the sulfoxide (ii) which can be further oxidized with anoxidant, such as mCPBA or H₂O₂ or dioxirane, to give the sulfone (iii).

Compounds of Formula (I) can be formed as shown in Scheme XI. Thecarbonyl of tricyclic (i) can be converted to the thiocarbonyl withLawesson's reagent to give compounds of Formula (I) (ii).

For the synthesis of particular compounds, the general schemes describedabove can be modified. For example, the products or intermediates can bemodified to introduce particular functional groups. Alternatively, thesubstituents can be modified at any step of the overall synthesis bymethods know to one skilled in the art, e.g., as described by Larock,Comprehensive Organic Transformations: A Guide to Functional GroupPreparations (Wiley, 1999); and Katritzky et al. (Ed.), ComprehensiveOrganic Functional Group Transformations (Pergamon Press 1996).

Starting materials, reagents and intermediates whose synthesis is notdescribed herein are either commercially available, known in theliterature, or may be prepared by methods known to one skilled in theart.

It will be appreciated by one skilled in the art that the processesdescribed are not the exclusive means by which compounds of theinvention may be synthesized and that a broad repertoire of syntheticorganic reactions is available to be potentially employed insynthesizing compounds of the invention. The person skilled in the artknows how to select and implement appropriate synthetic routes. Suitablesynthetic methods of starting materials, intermediates and products maybe identified by reference to the literature, including referencesources such as: Advances in Heterocyclic Chemistry, Vols. 1-107(Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49(Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.)Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge UpdatesKU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky, et al.(Ed.) Comprehensive Organic Functional Group Transformations, (PergamonPress, 1996); Katritzky et al. (Ed.); Comprehensive Organic FunctionalGroup Transformations II (Elsevier, 2^(nd) Edition, 2004); Katritzky etal. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984);Katritzky et al., Comprehensive Heterocyclic Chemistry II, (PergamonPress, 1996); Smith et al., March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley, 2007); Trost etal. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

III. Uses of the Compounds

Compounds of the invention are BET protein inhibitors and, thus, areuseful in treating diseases and disorders associated with activity ofBET proteins. For the uses described herein, any of the compounds of theinvention, including any of the embodiments thereof, may be used.

The compounds of the invention can inhibit one or more of BET proteinsBRD2, BRD3, BRD4, and BRD-t. In some embodiments, the compounds of theinvention selectively inhibit one or more BET proteins over another.“Selective” means that the compound binds to or inhibits a BET proteinwith greater affinity or potency, respectively, compared to a reference,such as another BET protein. For example, the compounds can be selectivefor BRD2 over BRD3, BRD4 and BRD-t, selective for BRD3 over BRD2, BRD4and BRD-t, selective for BRD4 over BRD2, BRD3 and BRD-t, or selectivefor BRD-t over BRD2, BRD3 and BRD4. In some embodiments, the compoundsinhibit two or more of the BET proteins, or all of the BET proteins. Ingeneral, selectivity can be at least about 5-fold, at least about10-fold, at least about 20-fold, at least about 50-fold, at least about100-fold, at least about 200-fold, at least about 500-fold or at leastabout 1000-fold.

The compounds of the invention are therefore useful for treating BETprotein mediated disorders. The term “BET-mediated” refers to anydisease or condition in which one or more of the BET proteins, such asBRD2, BRD3, BRD4 and/or BRD-t, or a mutant thereof, plays a role, orwhere the disease or condition is associated with expression or activityof one or more of the BET proteins. The compounds of the invention cantherefore be used to treat or lessen the severity of diseases andconditions where BET proteins, such as BRD2, BRD3, BRD4, and/or BRD-t,or a mutant thereof, are known to play a role.

Diseases and conditions treatable using the compounds of the inventioninclude, but are not limited to, cancer and other proliferativedisorders, autoimmune disease, chronic inflammatory diseases, acuteinflammatory diseases, sepsis, and viral infection. The diseases can betreated by administering to an individual (e.g., a patient) in need ofthe treatment a therapeutically effective amount or dose of a compoundof the invention, or any of the embodiments thereof, or a pharmaceuticalcomposition thereof. The present disclosure also provides a compound ofthe invention, or any of the embodiments thereof, or a pharmaceuticalcomposition thereof, for use in treating a BET-mediated disease ordisorder. Also provided is the use of a compound of the invention, orany of the embodiments thereof, or a pharmaceutical composition thereof,in the manufacture of a medicament for treating a BET-mediated diseaseor disorder.

Diseases that can be treated with the compounds of the invention includecancers. The cancers can include, but are not limited to, adrenalcancer, acinic cell carcinoma, acoustic neuroma, acral lentiginousmelanoma, acrospiroma, acute eosinophilic leukemia, acute erythroidleukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia,acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma,adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor,adenosquamous carcinoma, adipose tissue neoplasm, adrenocorticalcarcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia,AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft partsarcoma, ameloblastic fibroma, anaplastic large cell lymphoma,anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma,angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoidtumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocyticleukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer,bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor,Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma insitu, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma,chondroma, chordoma, choriocarcinoma, choroid plexus papilloma,clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-celllymphoma, cervical cancer, colorectal cancer, Degos disease,desmoplastic small round cell tumor, diffuse large B-cell lymphoma,dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonalcarcinoma, endocrine gland neoplasm, endodermal sinus tumor,enteropathy-associated T-cell lymphoma, esophageal cancer, fetus infetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroidcancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor,gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumorof the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosiscerebri, glucagonoma, gonadoblastoma, granulosa cell tumor,gynandroblastoma, gallbladder cancer, gastric cancer, hairy cellleukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma,hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma,intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna,lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lungcancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma,acute lymphocytic leukemia, acute myelogenous leukemia, chroniclymphocytic leukemia, liver cancer, small cell lung cancer, non-smallcell lung cancer, MALT lymphoma, malignant fibrous histiocytoma,malignant peripheral nerve sheath tumor, malignant triton tumor, mantlecell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia,mediastinal germ cell tumor, medullary carcinoma of the breast,medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkelcell cancer, mesothelioma, metastatic urothelial carcinoma, mixedMullerian tumor, mucinous tumor, multiple myeloma, muscle tissueneoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma,nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma,neuroma, nodular melanoma, ocular cancer, oligoastrocytoma,oligodendroglioma, oncocytoma, optic nerve sheath meningioma, opticnerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor,papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma,pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma,polyembryoma, precursor T-lymphoblastic lymphoma, primary centralnervous system lymphoma, primary effusion lymphoma, primary peritonealcancer, prostate cancer, pancreatic cancer, pharyngeal cancer,pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma,retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation,rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor,sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer,small blue round cell tumors, small cell carcinoma, soft tissue sarcoma,somatostatinoma, soot wart, spinal tumor, splenic marginal zonelymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease,small intestine cancer, squamous carcinoma, stomach cancer, T-celllymphoma, testicular cancer, thecoma, thyroid cancer, transitional cellcarcinoma, throat cancer, urachal cancer, urogenital cancer, urothelialcarcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visualpathway glioma, vulvar cancer, vaginal cancer, Waldenstrom'smacroglobulinemia, Warthin's tumor, and Wilms' tumor. In someembodiments, the cancer can be adenocarcinoma, adult T-cellleukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer,brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectalcancer, esophageal cancer, gastrointestinal cancer, glioblastomamultiforme, glioma, gallbladder cancer, gastric cancer, head and neckcancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer,kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, livercancer, small cell lung cancer, non-small cell lung cancer,mesothelioma, multiple myeloma, ocular cancer, optic nerve tumor, oralcancer, ovarian cancer, pituitary tumor, primary central nervous systemlymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renalcell carcinoma, rectal cancer, sarcoma, skin cancer, spinal tumor, smallintestine cancer, stomach cancer, T-cell lymphoma, testicular cancer,thyroid cancer, throat cancer, urogenital cancer, urothelial carcinoma,uterine cancer, vaginal cancer, or Wilms' tumor.

The diseases treatable using the compounds of the invention also includeMYC dependent cancers wherein the cancer is associated with at least oneof myc RNA expression or MYC protein expression. A patient can beidentified for such treatment by determining myc RNA expression or MYCprotein expression in the cancerous tissue or cells.

Diseases that can be treated with compounds of the invention alsoinclude non-cancerous proliferative disorders. Examples of proliferativedisorders that can be treated include, but are not limited to, benignsoft tissue tumors, bone tumors, brain and spinal tumors, eyelid andorbital tumors, granuloma, lipoma, meningioma, multiple endocrineneoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumorcerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cysticneoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, andcysts, Castleman disease, chronic pilonidal disease, dermatofibroma,pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.

The diseases and conditions that can be treated with the compounds ofthe invention also include chronic autoimmune and inflammatoryconditions. Examples of autoimmune and inflammatory conditions that canbe treated include acute, hyperacute or chronic rejection oftransplanted organs, acute gout, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),Addison's disease, agammaglobulinemia, allergic rhinitis, allergy,alopecia, Alzheimer's disease, appendicitis, atherosclerosis, asthma,osteoarthritis, juvenile arthritis, psoriatic arthritis, rheumatoidarthriti, satopic dermatitis, autoimmune alopecia, autoimmune hemolyticand thrombocytopenic states, autoimmune hypopituitarism, autoimmunepolyglandular disease, Behcet's disease, bullous skin diseases,cholecystitis, chronic idiopathic thrombocytopenic purpura, chronicobstructive pulmonary disease (COPD), cirrhosis, degenerative jointdisease, depression, dermatitis, dermatomyositis, eczema, enteritis,encephalitis, gastritis glomerulonephritis, giant cell arteritis,Goodpasture's syndrome, Guillain-Barre syndrome, gingivitis, Graves'disease, Hashimoto's thyroiditis, hepatitis, hypophysitis, inflammatorybowel disease (Crohn's disease and ulcerative colitis), inflammatorypelvic disease, irritable bowel syndrome, Kawasaki disease, LPS-inducedendotoxic shock, meningitis, multiple sclerosis, myocarditis, myastheniagravis, mycosis fungoides, myositis, nephritis, osteomyelitis,pancreatitis, Parkinson's disease, pericarditis, pernicious anemia,pneumonitis, primary biliary sclerosing cholangitis, polyarteritisnodosa, psoriasis, retinitis, scleritis, scleracierma, scleroderma,sinusitis, Sjogren's disease, sepsis, septic shock, sunburn, systemiclupus erythematosus, tissue graft rejection, thyroiditis, type Idiabetes, Takayasu's arteritis, urethritis, uveitis, vasculitis,vasculitis including giant cell arteritis, vasculitis with organinvolvement such as glomerulonephritis, vitiligo, Waldenstrommacroglobulinemia and Wegener's granulomatosis.

The diseases and conditions that can be treated with the compounds ofthe invention also include diseases and conditions which involveinflammatory responses to infections with bacteria, viruses, fungi,parasites or their toxins, such as sepsis, sepsis syndrome, septicshock, endotoxaemia, systemic inflammatory response syndrome (SIRS),multi-organ dysfunction syndrome, toxic shock syndrome, acute lunginjury, ARDS (adult respiratory distress syndrome), acute renal failure,fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes,sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis,malaria, SIRS associated with viral infections such as influenza, herpeszoster, herpes simplex and coronavirus.

Other diseases that can be treated with the compounds of the inventioninclude viral infections. Examples of viral infections that can betreated include Epstein-Barr virus, hepatitis B virus, hepatitis Cvirus, herpes virus, human immunodeficiency virus, human papillomavirus, adenovirus, poxvirus and other episome-based DNA viruses. Thecompounds can therefore be used to treat disease and conditions such asherpes simplex infections and reactivations, cold sores, herpes zosterinfections and reactivations, chickenpox, shingles, human papillomavirus, cervical neoplasia, adenovirus infections, including acuterespiratory disease, and poxvirus infections such as cowpox and smallpoxand African swine fever virus. In one particular embodiment, thecompounds of the invention are indicated for the treatment of humanpapilloma virus infections of skin or cervical epithelia.

The diseases and conditions that can be treated with the compounds ofthe invention also include conditions that are associated withischaemia-reperfusion injury. Examples of such conditions include, butare not limited to conditions such as myocardial infarction,cerebrovascular ischaemia (stroke), acute coronary syndromes, renalreperfusion injury, organ transplantation, coronary artery bypassgrafting, cardio-pulmonary bypass procedures and pulmonary, renal,hepatic, gastro-intestinal or peripheral limb embolism.

The compounds of the invention are also useful in the treatment ofdisorders of lipid metabolism via the regulation of APO-A1 such ashypercholesterolemia, atherosclerosis and Alzheimer's disease.

The compounds of the invention are also useful in the treatment offibrotic conditions such as idiopathic pulmonary fibrosis, renalfibrosis, post-operative stricture, keloid formation, scleroderma andcardiac fibrosis.

The compounds of the invention can also be used to treat ophthamologicalindications such as dry eye.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a BET protein with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having a BET protein, as wellas, for example, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the BETprotein.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) preventing the disease; for example, preventing a disease,condition or disorder in an individual who may be predisposed to thedisease, condition or disorder but does not yet experience or displaythe pathology or symptomatology of the disease; (2) inhibiting thedisease; for example, inhibiting a disease, condition or disorder in anindividual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology); and (3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

Combination Therapies

The compounds of the invention can be used in combination treatmentswhere the compound of the invention is administered in conjunction withother treatments such as the administration of one or more additionaltherapeutic agents. The additional therapeutic agents are typicallythose which are normally used to treat the particular condition to betreated. The additional therapeutic agents can include, e.g.,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, and JAK kinaseinhibitors for treatment of BET protein-associated diseases, disordersor conditions. The one or more additional pharmaceutical agents can beadministered to a patient simultaneously or sequentially.

In some embodiments, the compounds of the invention can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include the histone lysinemethyltransferases, histone arginine methyl transferases, histonedemethylases, histone deacetylases, histone acetylases, and DNAmethyltransferases. Histone deacetylase inhibitors include, e.g.,vorinostat.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with chemotherapeutic agents,or other anti-proliferative agents. The compounds of the invention canalso be used in combination with medical therapy such as surgery orradiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes. Examples of suitable chemotherapeutic agentsinclude any of: abarelix, aldesleukin, alemtuzumab, alitretinoin,allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase,azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib,busulfan intravenous, busulfan oral, calusterone, capecitabine,carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine,do farabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin,dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin,denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, andzoledronate.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with ruxolitinib.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with a corticosteroid suchas triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone,or flumetholone.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with an immune suppressantsuch as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol,Alcon), or cyclosporine (Restasis®).

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with one or more additionalagents selected from Dehydrex™ (Holles Labs), Civamide (Opko), sodiumhyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603,Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P)(Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen),15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine,doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301,Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali),oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101(2S,3S,4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl,Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences),ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15(Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4(RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31(Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551(Othera), PAI-2 (University of Pennsylvania and Temple University),pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednoletabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611(Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab,mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267(TorreyPines Therapeutics), or thalidomide.

In some embodiments, the compound of the invention can be administeredin combination with one or more agents selected from an antibiotic,antiviral, antifungal, anesthetic, anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatories, and anti-allergicagents. Examples of suitable medicaments include aminoglycosides such asamikacin, gentamycin, tobramycin, streptomycin, netilmycin, andkanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin,ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin;naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin;paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines;rifampin and its derivatives (“rifampins”); cycloserine; beta-lactams;cephalosporins; amphotericins; fluconazole; flucytosine; natamycin;miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen;ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; naphazoline;antazoline; pheniramine; or azalide antibiotic.

Other examples of agents, one or more of which a provided compound mayalso be combined with include: a treatment for Alzheimer's Disease suchas donepezil and rivastigmine; a treatment for Parkinson's Disease suchas L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine,pergolide, trihexyphenidyl, and amantadine; an agent for treatingmultiple sclerosis (MS) such as beta interferon (e.g., Avonex® andRebif®), glatiramer acetate, and mitoxantrone; a treatment for asthmasuch as albuterol and montelukast; an agent for treating schizophreniasuch as zyprexa, risperdal, seroquel, and haloperidol; ananti-inflammatory agent such as a corticosteroid, such as dexamethasoneor prednisone, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; an immunomodulatory agent, includingimmunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, an interferon, a corticosteroid,cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factorsuch as an acetylcholinesterase inhibitor, an MAO inhibitor, aninterferon, an anti-convulsant, an ion channel blocker, riluzole, or ananti-Parkinson's agent; an agent for treating cardiovascular diseasesuch as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, acalcium channel blocker, or a statin; an agent for treating liverdisease such as a corticosteroid, cholestyramine, an interferon, and ananti-viral agent; an agent for treating blood disorders such as acorticosteroid, an anti-leukemic agent, or a growth factor; or an agentfor treating immunodeficiency disorders such as gamma globulin.

IV. Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. The term “unit dosageforms” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

In some embodiments, the compositions of the invention contain fromabout 5 mg to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compounds orcompositions containing about 5 mg to about 10 mg, about 10 mg to about15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of theactive ingredient.

In some embodiments, the compositions of the invention contain fromabout 50 mg to about 500 mg of the active ingredient. One havingordinary skill in the art will appreciate that this embodies compoundsor compositions containing about 50 mg to about 100 mg, about 100 mg toabout 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about450 mg to about 500 mg of the active ingredient.

In some embodiments, the compositions of the invention contain fromabout 500 mg to about 1,000 mg of the active ingredient. One havingordinary skill in the art will appreciate that this embodies compoundsor compositions containing about 500 mg to about 550 mg, about 550 mg toabout 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg toabout 950 mg, or about 950 mg to about 1,000 mg of the activeingredient.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face masks tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% Aviv of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted hereinabove.

V. Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating BET proteins in tissuesamples, including human, and for identifying BET protein ligands byinhibition binding of a labeled compound. Accordingly, the presentinvention includes BET protein assays that contain such labeledcompounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ³H(also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I, and ¹³¹I. Theradionuclide that is incorporated in the instant radio-labeled compoundswill depend on the specific application of that radio-labeled compound.For example, for in vitro BET protein labeling and competition assays,compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, or ³⁵S willgenerally be most useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is to be understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵, ³⁵S and ⁸²Br. In some embodiments, the compoundincorporates 1, 2, or 3 deuterium atoms.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a BET protein by monitoring itsconcentration variation when contacting with the BET protein, throughtracking of the labeling. For example, a test compound (labeled) can beevaluated for its ability to reduce binding of another compound which isknown to bind to a BET protein (i.e., standard compound). Accordingly,the ability of a test compound to compete with the standard compound forbinding to the BET protein directly correlates to its binding affinity.Conversely, in some other screening assays, the standard compound islabeled and test compounds are unlabeled. Accordingly, the concentrationof the labeled standard compound is monitored in order to evaluate thecompetition between the standard compound and the test compound, and therelative binding affinity of the test compound is thus ascertained.

VI. Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of BET protein-associateddiseases or disorders, such as cancer, which include one or morecontainers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention. Suchkits can further include, if desired, one or more of variousconventional pharmaceutical kit components, such as, for example,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof one or more BET proteins as described below.

EXAMPLES Example 19-(3,5-Dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one

Step 1. Methyl 4-bromo-3-hydroxy-2-nitrobenzoate

A solution of 4-bromo-3-hydroxybenzoic acid (6.00 g, 27.6 mmol) [CombiBlocks, CA-4188] in sulfuric acid (138 mL) was stirred at 20° C. for 30min, cooled to 0° C., and treated with a chilled (cooled with ice bath)solution of fuming nitric acid (1.39 mL, 33.2 mmol)/sulfuric acid (69.1mL) dropwise. The reaction mixture was stirred at 0° C. for 30 min,quenched by pouring over ice, and extracted with ethyl acetate (2×250mL). The combined organic extracts were washed with brine, dried oversodium sulfate, filtered, and concentrated to give the desired nitrointermediate (7.41 g, >100%) that was used without further purification.LCMS calculated for C₇H₈BrN₂O₅ (M+NH₄)⁺: m/z=279.0, 281.0. found: 279.0,280.9.

The crude nitro intermediate was dissolved in methanol (110 mL), cooledto 0° C. and treated with thionyl chloride (9.08 mL, 124 mmol) dropwise.After addition the ice bath was removed and after warming to ambienttemperature the solution was heated at 70° C. for 16 h. The reactionmixture was concentrated to a tan solid. Purification by flash columnchromatography (100% hexanes to 70% EtOAc [containing 5% methanol]/30%hexanes) gave the desired product (5.41 g, 71%) as a tan solid. LCMScalculated for C₈H₁₀BrN₂O₅ (M+NH₄)⁺: m/z=293.0, 295.0. found: 293.0,294.9.

Step 2. Methyl 3-(benzyloxy)-4-bromo-2-nitrobenzoate

A solution of methyl 4-bromo-3-hydroxy-2-nitrobenzoate (5.41 g, 19.6mmol) and potassium carbonate (5.42 g, 39.2 mmol) inN,N-dimethylformamide (30 mL, 387 mmol) was treated with benzyl bromide(3.26 mL, 27.4 mmol) and stirred at 60° C. for 1 h. The reaction mixturewas diluted with water (250 mL) and extracted with ethyl acetate (2×150mL). The combined organic extracts were washed with brine, dried oversodium sulfate, filtered, and concentrated to give a crude tan oil.Purification by flash column chromatography (100% hexanes to 50%EtOAc/hexanes) gave the desired product (6.99 g, 97%) as a yellow solid.LCMS calculated for C₁₅H₁₆BrN₂O₅ (M+NH₄)⁺: m/z=383.0, 385.0. found:383.0, 385.0.

Step 3. Methyl3-(benzyloxy)-4-(3,5-dimethylisoxazol-4-yl)-2-nitrobenzoate and methyl4-(3,5-dimethylisoxazol-4-yl)-3-hydroxy-2-nitrobenzoate

A mixture of methyl 3-(benzyloxy)-4-bromo-2-nitrobenzoate (6.49 g, 17.7mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (6.24 g, 44.3 mmol)[Matrix Scientific, 004078], and potassium carbonate (9.80 g, 70.9 mmol)in 1,4-dioxane (69.5 mL) and water (34.8 mL) was degassed with nitrogenfor 10 min. The reaction mixture was treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (1.45 g, 1.77 mmol), degassed with nitrogenfor another 5 min, and heated at 80° C. for 1 h. The reaction mixturewas filtered through Celite and the solids washed with EtOAc (200 mL).The filtrated was washed with water (200 mL), brine (100 mL), dried oversodium sulfate, filtered, and concentrated to give a brown oil. Theaqueous layer from the first 200 mL wash contained the desired productthat had lost the benzyl group. This was cooled to 0° C., acidified with6 M HCl, and extracted with EtOAc (100 mL) to provide a brown oil. Thetwo products were purified separately. Purification of the first batchby flash column chromatography (100% hexanes to 50% EtOAc [containing 5%methanol]/50% hexanes) gave the desired product, methyl3-(benzyloxy)-4-(3,5-dimethylisoxazol-4-yl)-2-nitrobenzoate, (5.13 g,76%) as a yellow solid. LCMS calculated for C₂₀H₁₉N₂O₆ (M+H)⁺:m/z=383.1. found: 383.1. Purification of the second batch by flashcolumn chromatography (100% hexanes to 80% EtOAc [containing 5%methanol]/20% hexanes) gave the desired product minus the benzyl group,methyl 4-(3,5-dimethylisoxazol-4-yl)-3-hydroxy-2-nitrobenzoate, (0.63 g,12%) as a white solid. LCMS calculated for C₁₃H₁₃N₂O₆ (M+H)⁺: m/z=293.1.found: 293.0.

Step 4. Methyl 2-amino-4-(3,5-dimethylisoxazol-4-yl)-3-hydroxybenzoate

A suspension of methyl3-(benzyloxy)-4-(3,5-dimethylisoxazol-4-yl)-2-nitrobenzoate (0.959 g,2.51 mmol) in methanol (49.9 mL) was degassed with nitrogen, treatedwith 10% Pd/C, Degussa type, (0.144 g), and hydrogenated with a balloonof hydrogen for 1 h. A solution formed during the first 30 min. Thereaction mixture was filtered through a cartridge and the solids werewashed with methanol. The filtrate was concentrated to give the desiredproduct (0.656 g, quantitative) as an orange solid that was used withoutfurther purification. LCMS calculated for C₁₃H₁₅N₂O₄ (M+H)⁺: m/z=263.1.found: 263.1.

Alternatively, methyl4-(3,5-dimethylisoxazol-4-yl)-3-hydroxy-2-nitrobenzoate, from Step 3,can be treated in the same fashion to give methyl2-amino-4-(3,5-dimethylisoxazol-4-yl)-3-hydroxybenzoate in quantitativeyield.

Step 5. Methyl8-(3,5-dimethylisoxazol-4-yl)-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate

A solution of methyl2-amino-4-(3,5-dimethylisoxazol-4-yl)-3-hydroxybenzoate (0.656 g, 2.50mmol) and potassium carbonate (0.691 g, 5.00 mmol) inN,N-dimethylformamide (7.5 mL) was treated with 2-bromoacetophenone(0.572 g, 2.88 mmol) and stirred for 30 min. The reaction mixture waspoured into water (100 mL) and extracted with ethyl acetate (100 mL).The organic layer was separated, washed with brine, dried over sodiumsulfate, filtered, and concentrated to give the intermediate imine as atan foam that was used without further purification. The crudeintermediate imine was dissolved in methanol (25 mL) and treated withacetic acid (0.284 mL, 5.00 mmol). The solution was degassed withnitrogen, treated with 10% Pd/C, Degussa type, (0.131 g), andhydrogenated with a balloon of hydrogen for 1 h. Due to incompletereaction, the mixture was treated with additional 10% Pd/C, Degussatype, (0.066 g) and hydrogenated with a balloon of hydrogen for another1 h. The reaction mixture was filtered through a cartridge and thesolids were washed with methanol, ethyl acetate, and dichloromethane.The filtrate was concentrated to give the crude product. Purification byflash column chromatography (100% hexanes to 60% EtOAc/hexanes) gave thedesired product (0.661 g, 73%) as a yellow solid. LCMS calculated forC₂₁H₂₁N₂O₄ (M+H)⁺: m/z=365.1. found: 365.1.

Step 6. Methyl8-(3,5-dimethylisoxazol-4-yl)-4-nitroso-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate

A suspension of methyl8-(3,5-dimethylisoxazol-4-yl)-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate(0.230 g, 0.631 mmol) in ethyl acetate (6.13 mL) was cooled to 0° C. andtreated with 6.0 M hydrogen chloride in water (0.789 mL, 4.73 mmol) andwater (0.460 mL) followed by sodium nitrite (0.0871 g, 1.26 mmol) inwater (0.690 mL) dropwise. The reaction mixture was stirred at 0° C. for15 min, the ice bath was removed, and stirred for 30 min which gave abiphasic solution. After another 30 min a suspension was present. Thereaction mixture was diluted with EtOAc (40 mL) and water (20 mL). Theorganic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated to give a crude tan solid. Purification byflash column chromatography (100% hexanes to 50% EtOAc/hexanes) gave thedesired product (0.228 g, 92%) as a yellow solid. LCMS calculated forC₂₁H₂₀N₂O₄ ([M−NO]+H)⁺: m/z=364.1. found: 364.1.

Step 7.9-(3,5-Dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one

A suspension of methyl8-(3,5-dimethylisoxazol-4-yl)-4-nitroso-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate(0.228 g, 0.580 mmol) in ethyl acetate (4.04 mL) and methanol (4.04 mL)at 0° C. was treated with saturated aqueous ammonium chloride solution(2.02 mL, 30.2 mmol) and then zinc (0.303 g, 4.64 mmol) was added inthree portions over 6 min. The cooling bath was removed and the reactionmixture was stirred for 2 h. The reaction mixture was diluted with ethylacetate (30 mL), filtered through a Celite pad, and rinsed with ethylacetate (2×10 mL). The filtrate was washed with water (20 mL), brine,(20 mL), dried over sodium sulfate, filtered, and concentrated to give acrude tan foam. Purification by flash column chromatography (100%dichloromethane to 10% methanol/dichloromethane) gave the desiredproduct (0.14 g, 70%) as a yellow foam. ¹H NMR (500 MHz, DMSO-d₆) δ10.98 (br s, 1H), 7.40-7.29 (m, 3H), 7.26 (d, J=8.3 Hz, 1H), 7.23-7.15(m, 2H), 6.87 (d, J=8.2 Hz, 1H), 5.39 (br s, 1H), 4.74 (dd, J=11.5, 3.1Hz, 1H), 4.61 (dd, J=11.5, 5.8 Hz, 1H), 2.31 (s, 3H), 2.15 (s, 3H). LCMScalculated for C₂₀H₁₈N₃O₃ (M+H)⁺: m/z=348.1. found: 348.1.

Example 29-(3,5-Dimethylisoxazol-4-yl)-5-methyl-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-oneand Example 39-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole

A solution of9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one(0.030 g, 0.086 mmol) in N,N-dimethylformamide (0.41 mL) was treatedwith sodium hydride (6.91 mg, 0.173 mmol) and stirred for 2 h. Thereaction mixture was treated with methyl iodide (7.0 μL, 0.112 mmol) andstirred for 1 h. The reaction mixture was cooled to 0° C. and quenchedwith saturated ammonium chloride solution. The aqueous solution wasextracted with ethyl acetate to give a crude tan solid. Purification viapreparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of30 mL/min) gave Example 2 (1.3 mg, 4%, first peak to elute) and Example3 (2 mg, 6%, second peak to elute) (two separate passes through thepreparative LCMS system was needed to isolate both peaks). Example 2: ¹HNMR (500 MHz, CDCl₃) δ 7.48-7.39 (m, 4H), 7.37-7.30 (m, 2H), 6.97 (d,J=8.0 Hz, 1H), 4.74 (dd, J=11.9, 8.2 Hz, 1H), 4.55 (dd, J=12.0, 3.0 Hz,1H), 4.34 (dd, J=8.1, 2.8 Hz, 1H), 2.95 (s, 3H), 2.35 (s, 3H), 2.23 (s,3H); LCMS calculated for C₂₁H₂₀N₃O₃ (M+H)⁺: m/z=362.1. found: 362.1.Example 3: 1H NMR (500 MHz, CDCl₃) δ 7.39-7.30 (m, 3H), 7.27 (d, J=8.3Hz, 1H), 7.18-7.10 (m, 2H), 6.81 (d, J=8.3 Hz, 1H), 5.37 (dd, J=5.4, 3.4Hz, 1H), 4.67 (dd, J=11.4, 3.4 Hz, 1H), 4.51 (dd, J=11.5, 5.5 Hz, 1H),4.04 (s, 3H), 2.34 (s, 3H), 2.23 (s, 3H); LCMS calculated for C₂₁H₂₀N₃O₃(M+H)⁺: m/z=362.1. found: 362.1.

Example 49-(3,5-Dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole

Step 1.[8-(3,5-Dimethylisoxazol-4-yl)-3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-5-yl]methanol

A solution of methyl8-(3,5-dimethylisoxazol-4-yl)-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate(0.150 g, 0.412 mmol) in tetrahydrofuran (4.50 mL) at 0° C. was treatedwith 1.0 M lithium tetrahydroaluminate in THF (0.823 mL, 0.823 mmol)dropwise. After complete addition the mixture was stirred at 0° C. for15 min. The reaction mixture was quenched with saturated ammoniumchloride solution (20 mL), warmed to R.T., and extracted with ethylacetate (2×20 mL). The combined organic extracts were dried over sodiumsulfate, filtered, and concentrated to give a colorless residue.Purification by flash column chromatography (100% hexanes to 70% EtOAc[containing 5% methanol]/30% hexanes) gave the desired product (0.13 g,94%) as a white foam. LCMS calculated for C₂₀H₂₁N₂O₃ (M+H)⁺: m/z=337.2.found: 337.2.

Step 2.[4-Amino-8-(3,5-dimethylisoxazol-4-yl)-3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-5-yl]methanol

A solution of[8-(3,5-dimethylisoxazol-4-yl)-3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-5-yl]methanol(0.129 g, 0.383 mmol) in ethyl acetate (2.79 mL) at 0° C. was treatedwith water (0.42 mL) and 6.0 M hydrogen chloride in water (0.479 mL,2.88 mmol) followed by sodium nitrite (40 mg, 0.575 mmol) in water (0.28mL). The reaction mixture was stirred at 0° C. for 30 min and dilutedwith ethyl acetate (30 mL) and water (20 mL). The organic layer wasseparated, washed with brine, dried over sodium sulfate, filtered, andconcentrated to give the intermediate nitroso compound that was usedimmediately without further purification. The crude intermediate wasdissolved in tetrahydrofuran (2.25 mL), cooled to 0° C., treated with1.0 M lithium tetrahydroaluminate in THF (0.767 mL, 0.767 mmol), andstirred at 0° C. for 30 min. The reaction mixture was quenched withsaturated ammonium chloride solution, warmed to R.T., and extracted withethyl acetate (2×30 mL). The combined organic extracts were washed withbrine, dried over sodium sulfate, filtered, and concentrated to give atan foam. Purification by flash column chromatography (100% hexanes to70% EtOAc [containing 5% methanol]/30% hexanes) gave the desired product(88 mg, 65%) as a tan foam. LCMS calculated for C₂₀H₂₂N₃O₃ (M+H)⁺:m/z=352.2. found: 352.2.

Step 3.9-(3,5-Dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole

A solution of 2.0 M oxalyl chloride in methylene chloride (0.132 mL) at−78° C. was treated with methylene chloride (0.363 mL) followed bydimethyl sulfoxide (0.025 mL, 0.353 mmol) dropwise. The reaction mixturewas stirred at −78° C. for 20 min and treated with a solution of[4-amino-8-(3,5-dimethylisoxazol-4-yl)-3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-5-yl]methanol(0.062 g, 0.18 mmol) in methylene chloride (1.50 mL) dropwise. Thereaction mixture was stirred at −78° C. for 1 h and treated withtriethylamine (0.0984 mL, 0.706 mmol) dropwise. The reaction mixture wasstirred at −78° C. for 1 h and warmed to 25° C. The reaction mixture wasquenched with water (2 mL) and diluted with methylene chloride (30 mL)and saturated ammonium chloride solution (10 mL). The organic layer wasseparated, washed with brine, dried over sodium sulfate, filtered, andconcentrated to give a tan foam. Purification via preparative LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gavethe desired product (19 mg, 32%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.13 (s,1H), 7.43 (d, J=8.3 Hz, 1H), 7.39-7.30 (m, 3H), 7.13-7.06 (m, 2H), 7.03(d, J=8.3 Hz, 1H), 5.90 (dd, J=3.9 Hz, 1H), 4.79 (dd, J=11.6, 3.4 Hz,1H), 4.69 (dd, J=11.6, 4.6 Hz, 1H), 2.32 (s, 3H), 2.16 (s, 3H). LCMScalculated for C₂₀H₁₈N₃O₂ (M+H)⁺: m/z=332.1. found: 332.1.

Example 59-(3,5-Dimethylisoxazol-4-yl)-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one

Example 5 was made according to the procedure of Example 1 using2-bromo-1-pyridin-2-ylethanone hydrobromide instead of2-bromoacetophenone in Step 5. ¹H NMR (300 MHz, DMSO-d₆) δ 11.06 (br s,1H), 8.56 (d, J=4.7 Hz, 1H), 7.82-7.69 (m, 1H), 7.33 (dd, J=7.1, 5.1 Hz,1H), 7.28 (d, J=8.3 Hz, 1H), 6.86 (d, J=8.3 Hz, 2H), 5.52 (br s, 1H),4.81 (d, J=3.6 Hz, 2H), 2.28 (s, 3H), 2.12 (s, 3H); LCMS calculated forC₁₉H₁₇N₄O₃ (M+H)⁺: m/z=349.1. found: 349.1.

Example 69-(3,5-Dimethylisoxazol-4-yl)-5-methyl-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-oneand Example 79-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole

A solution of9-(3,5-dimethylisoxazol-4-yl)-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one(0.03 g, 0.086 mmol) in N,N-dimethylformamide (0.24 mL) at 0° C. wastreated with potassium carbonate (0.024 g, 0.172 mmol) followed bydropwise addition of 0.2 M methyl iodide in N,N-dimethylformamide (0.517mL, 0.103 mmol) and stirred at 0° C. for 30 min. The ice bath wasremoved and the reaction mixture was stirred for 1 h. The reactionmixture was treated with water (20 mL) and extracted with EtOAc (30 mL).The organic layer was separated and washed with brine (10 mL), driedover sodium sulfate, filtered, and concentrated to give a colorlessresidue. Purification by preparative LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) gave Example 6 (10 mg, 30%, firstpeak to elute) and Example 7 (8 mg, 20%, second peak to elute). Example6: ¹H NMR (500 MHz, DMSO-d₆) δ 8.47 (d, J=4.4 Hz, 1H), 7.86-7.71 (m,1H), 7.38-7.29 (m, 1H), 7.29-7.21 (m, 2H), 7.00 (d, J=8.0 Hz, 1H), 5.14(dd, J=3.4 Hz, 1H), 4.93 (d, J=3.5 Hz, 2H), 3.08 (s, 3H), 2.30 (s, 3H),2.13 (s, 3H); LCMS calculated for C₂₀H₁₉N₄O₃ (M+H)⁺: m/z=363.1. found:363.1. Example 7: ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (d, J=4.1 Hz, 1H),7.82-7.68 (m, 1H), 7.33 (dd, J=7.0, 5.2 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H),6.91 (d, J=8.3 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 5.76-5.66 (m, 1H),4.93-4.73 (m, 2H), 3.99 (s, 3H), 2.27 (s, 3H), 2.11 (s, 3H); LCMScalculated for C₂₀H₁₉N₄O₃ (M+H)⁺: m/z=363.1. found: 363.1.

Example 89-(3,5-Dimethylisoxazol-4-yl)-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazoletrifluoroacetate

The compound of Example 8 was made according to the procedure of Example4 using methyl8-(3,5-dimethylisoxazol-4-yl)-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylateinstead of8-(3,5-dimethylisoxazol-4-yl)-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylatein Step 1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (d, J=4.2 Hz, 1H), 8.17 (s,1H), 7.79-7.71 (m, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.34 (dd, J=6.9, 4.9 Hz,1H), 7.02 (d, J=8.3 Hz, 1H), 6.77 (d, J=7.9 Hz, 1H), 6.05-5.97 (m, 1H),4.92 (dd, J=11.5, 3.4 Hz, 1H), 4.82 (dd, J=11.5, 3.3 Hz, 1H), 2.29 (s,3H), 2.13 (s, 3H); LCMS calculated for C₁₉H₁₇N₄O₂ (M+H)⁺: m/z=333.1.found: 333.1.

Example 97-Bromo-9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole

A solution of9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole(0.011 g, 0.033 mmol) in acetonitrile (0.4 mL) at 0° C. was treated withN-bromosuccinimide (8.3 mg, 0.047 mmol) and stirred at 0° C. for 30 min.The reaction mixture was diluted with EtOAc (20 mL) and washed withsaturated sodium bicarbonate solution (20 mL), dried over sodiumsulfate, filtered, and concentrated to a colorless residue. Purificationvia preparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of30 mL/min) gave desired product (9 mg, 70%). ¹H NMR (300 MHz, DMSO-d₆) δ8.11 (s, 1H), 7.40-7.32 (m, 3H), 7.28 (s, 1H), 7.16-7.05 (m, 2H),5.99-5.89 (m, 1H), 4.81 (dd, J=11.7, 3.4 Hz, 1H), 4.71 (dd, J=11.6, 4.8Hz, 1H), 2.32 (s, 3H), 2.16 (s, 3H); LCMS calculated for C₂₀H₁₇BrN₃O₂(M+H)⁺: m/z=410.0, 412.0. found: 410.0, 412.0.

Example 109-(3,5-Dimethylisoxazol-4-yl)-3-pyridin-3-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one

The compound of Example 10 was made according to the procedure ofExample 1 using 2-bromo-1-pyridin-3-ylethanone hydrobromide instead of2-bromoacetophenone in step 5. ¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (br s,1H), 8.58 (br s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.58 (dd, J=7.6, 4.9 Hz,1H), 7.29 (d, J=8.3 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 5.48 (br s, 1H),4.81 (dd, J=11.5, 3.3 Hz, 1H), 4.72 (dd, J=11.6, 6.0 Hz, 1H), 2.32 (s,3H), 2.16 (s, 3H); LCMS calculated for C₁₉H₁₇N₄O₃ (M+H)⁺: m/z=349.1.found: 349.1.

Example 119-(3,5-Dimethylisoxazol-4-yl)-5-methyl-3-pyridin-3-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one

and

Example 129-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-pyridin-3-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole

The compounds of Example 11 and Example 12 were made according to theprocedure of Examples 6 and 7 using9-(3,5-dimethylisoxazol-4-yl)-3-pyridin-3-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-oneinstead of 9-(3,5-dimethylisoxazol-4-yl)-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one. Example 11 (first peak to elute):¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (d, J=3.9 Hz, 1H), 8.51 (s, 1H), 7.61(d, J=8.0 Hz, 1H), 7.40 (dd, J=7.8, 4.8 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H),7.09 (d, J=8.0 Hz, 1H), 5.08-4.98 (m, 1H), 4.96-4.84 (m, 2H), 3.01 (s,3H), 2.33 (s, 3H), 2.16 (s, 3H); LCMS calculated for C₂₀H₁₉N₄O₃ (M+H)⁺:m/z=363.1. found: 363.1. Example 12 (second peak to elute): ¹H NMR (400MHz, DMSO-d₆) δ 8.55 (d, J=3.8 Hz, 1H), 8.42 (s, 1H), 7.53 (d, J=8.0 Hz,1H), 7.40 (dd, J=7.8, 4.8 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 6.94 (d,J=8.3 Hz, 1H), 5.73-5.59 (m, 1H), 4.82 (dd, J=11.6, 3.2 Hz, 1H), 4.71(dd, J=11.6, 5.1 Hz, 1H), 3.95 (s, 3H), 2.31 (s, 3H), 2.15 (s, 3H); LCMScalculated for C₂₀H₁₉N₄O₃ (M+H)⁺: m/z=363.1. found: 363.1.

Example 137-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydro[1,2,3]triazolo[1,5,4-de][1,4]benzoxazinetrifluoroacetate

Step 1. 6-Bromo-4-fluoro-2,3-dinitrophenol

To a solution of 2-bromo-4-fluoro-5-nitrophenol (4.0 g, 17 mmol) (Ark #AK-27735) in methylene chloride (29.5 mL), 2.0 M nitric acid inmethylene chloride (25 mL) was added and the mixture was stirred for 15min at RT. The mixture was poured into ice-cold water and extracted withmethylene chloride to give the crude product, 4.42 g, 93%.

Step 2. 2-Amino-6-bromo-4-fluoro-3-nitrophenol

To a stirred solution of 6-bromo-4-fluoro-2,3-dinitrophenol (4.4 g, 16mmol) in methanol (88 mL) and 12.0 M hydrogen chloride in water (40 mL)was added stannous chloride, dihydrate (11 g, 47 mmol). The reaction wasstirred at RT for 15 min. Water was added and the mixture was extractedwith ethyl acetate. The organic layer was separated and concentrated.Purification on silica gel using ethyl acetate in hexanes gave thedesired compound, 2.48 g, 63%. ¹H NMR (300 MHz, DMSO-d₆) δ 9.80 (br s,3H), 6.80 (m, 1H).

Step 3.8-Bromo-6-fluoro-5-nitro-3-pyridin-3-yl-3,4-dihydro-2H-1,4-benzoxazin-3-ol

2-Amino-6-bromo-4-fluoro-3-nitrophenol (500 mg, 1.9 mmol) and potassiumcarbonate (780 mg, 5.7 mmol) were stirred in acetone (8 mL) for 5minutes and 2-bromo-1-pyridin-3-ylethanone hydrobromide (530 mg, 1.9mmol) was added as a solid over 5 minutes. The mixture was stirred at rtfor 5 minutes and poured into water. The mixture was extracted withethyl acetate. The extracts were washed with brine, dried over sodiumsulfate, filtered and evaporated. Purification on silica gel using ethylacetate in hexanes gave the desired compound, 0.69 g, 99%. LCMScalculated for C₁₃H₁₀BrFN₃O₄ (M+H)⁺: m/z=370.1, 372.1. found: 370.0,372.0.

Step 4. 8-Bromo-6-fluoro-3-pyridin-3-yl-2H-1,4-benzoxazin-5-amine

To8-bromo-6-fluoro-5-nitro-3-pyridin-3-yl-3,4-dihydro-2H-1,4-benzoxazin-3-ol(690 mg, 1.9 mmol) in acetic acid (20 mL), iron (520 mg, 9.4 mmol) wasadded and heated at 60° C. overnight. The reaction was extracted withethyl acetate to give the crude product, 0.60 g, 100%. ¹H NMR (300 MHz,DMSO-d₆) δ 9.28 (s, 1H), 8.68 (m, 1H), 8.51 (m, 1H), 7.52 (m, 1H), 6.89(m, 1H), 5.80 (s, 2H), 5.13 (s, 2H), 2.25 (s, 3H), 2.10 (s, 3H). LCMScalculated for C₁₃H₁₀BrFN₃O (M+H)⁺: m/z=322.0, 324.0. found: 321.8,323.8.

Step 5.8-(3,5-Dimethylisoxazol-4-yl)-6-fluoro-3-pyridin-3-yl-2H-1,4-benzoxazin-5-amine

4-(Di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1)(3.3 mg, 0.0047 mmol) and cesium fluoride (83 mg, 0.54 mmol),8-bromo-6-fluoro-3-pyridin-3-yl-2H-1,4-benzoxazin-5-amine (50 mg, 0.2mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (33 mg, 0.23 mmol)were stirred in 1-butanol (0.50 mL) and water (0.12 mL). The system wasplaced under vacuum and back-filled with nitrogen (repeated 3×) whilestirring the suspension. The mixture was further degassed by bubblingnitrogen through the solution for 10 minutes. The mixture was heated at100° C. for 1 hour. Extractive workup with ethyl acetate gave thedesired compound 40 mg, 80%. ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H),8.68 (m, 1H), 8.51 (m, 1H), 7.52 (m, 1H), 6.89 (m, 1H), 5.80 (s, 2H),5.13 (s, 2H), 2.25 (s, 3H), 2.10 (s, 3H). LCMS calculated forC₁₈H₁₆FN₄O₂ (M+H)⁺: m/z=339.1. found: 339.0.

Step 6.8-(3,5-Dimethylisoxazol-4-yl)-6-fluoro-3-pyridin-3-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine

To a solution of8-(3,5-dimethylisoxazol-4-yl)-6-fluoro-3-pyridin-3-yl-2H-1,4-benzoxazin-5-amine(40 mg, 0.1 mmol) in ethanol (0.8 mL) and water (0.2 mL), sodiumtetrahydroborate (4.5 mg, 0.12 mmol) was added and the mixture washeated at 90° C. for 15 minutes. Sodium tetrahydroborate (4.5 mg, 0.12mmol) was added and the mixture was heated to 90° C. for 15 minutesagain. The mixture was evaporated and extracted with ethyl acetate. Theorganic extracts were evaporated. Purification by preparative LCMS (pH10) gave the desired compound 11 mg, 30%. ¹H NMR (300 MHz, DMSO-d₆) δ8.62 (s, 1H), 8.50 (m, 1H), 7.80 (m, 1H), 7.40 (m, 1H), 6.35 (m, 1H),5.61 (s, 1H), 4.78 (s, 2H), 4.60 (m, 1H), 4.20 (m, 1H), 3.98 (m, 1H),2.20 (s, 3H), 2.01 (s, 3H). LCMS calculated for C₁₈H₁₈FN₄O₂ (M+H)⁺:m/z=341.1. found: 340.9.

Step 7.7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydro[1,2,3]triazolo[1,5,4-de][1,4]benzoxazinetrifluoroacetate

To a solution of8-(3,5-dimethylisoxazol-4-yl)-6-fluoro-3-pyridin-3-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine(9.0 mg, 0.026 mmol) in 5.0 M hydrogen chloride in water (0.26 mL, 1.3mmol) at 0° C., was added a solution of sodium nitrite (3.6 mg, 0.053mmol) in water (100 μL). The reaction mixture was stirred at 0° C. for10 min and at RT for 20 minutes. Purification by preparative LCMS (pH 2)gave the desired compound, 7 mg, 60%. ¹H NMR (300 MHz, DMSO-d₆) δ 8.62(m, 2H), 7.79 (m, 1H), 7.50 (m, 1H), 7.29 (m, 1H), 6.41 (m, 1H), 4.92(m, 1H), 4.79 (m, 1H), 2.37 (s, 3H), 2.20 (s, 3H). LCMS calculated forC₁₈H₁₅FN₅O₂ (M+H)⁺: m/z=352.1. found: 351.9.

Biological Assay Protocols Example Assay A1 BRD4 AlphaScreen™ Assay

BRD4-BD1 and BRD4-BD2 assays were conducted in white 384-wellpolystyrene plate in a final volume of 20 μL for BD1 and 40 μL for BD2.Inhibitors were first serially diluted in DMSO and added to the platewells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 1.25% (BD1) and 0.83% (BD2). Theassays were carried out at room temperature for 75 min. in the assaybuffer (50 mM HEPES, pH 7.4, 100 mM NaCl, 0.05% CHAPS, 0.01% BSA),containing 50 nM Biotin-labeled tetra-acetylated histone H4 peptide(H4Ac4), 3.8 nM (BRD4-BD1, BPS Bioscience #31040) or 20 nM (BRD4-BD2,BPS Bioscience #31041). The reaction followed by the addition of 20 μLof assay buffer supplemented with Streptavidin donor beads (PerkinElmer6760002) and GSH Acceptor beads (PerkinElmer-AL109C) at 4 μg/mL underreduced light. After plate sealing, the plate was incubated in the darkat room temperature for 75 min. before reading on a PHERAstar FS platereader (BMG Labtech). IC₅₀ determination was performed by fitting thecurve of percent control activity versus the log of the inhibitorconcentration using the GraphPad Prism 5.0 software.

IC₅₀ data for the compounds of the Examples as determined by Assay A1 ispresented in Table 1.

TABLE 1 BRD4 BD-1 BRD4 BD-2 Example enzyme IC₅₀ enzyme IC₅₀ No. (nM)*(nM)* 1 + + 2 + + 3 + + 4 + + 5 ++ + 6 + + 7 + + 8 + + 9 ++ + 10 ++ +11 + + 12 + + 13 +++ ++ *Symbols used: +: IC₅₀ ≦ 200 nM ++: 200 nM <IC₅₀ ≦ 1000 nM +++: IC₅₀ > 1000 nM

Example Assay B1 KMS.12.BM Cell Viability Assay

KMS.12.BM cell line (human myeloma) was purchased from JCRB (Osaka,Japan) and maintained in RPMI with 10% FBS culture medium. To measurethe cytotoxic activity of the compounds through ATP quantitation, theKMS.12.BM cells are plated in the RPMI culture medium at 5000cells/well/per 100 μL into a 96-well polystyrene clear black tissueculture plate (Greiner-bio-one through VWR, NJ), in the presence orabsence of a concentration range of test compounds. After 3 days, 100 mLCell Titer-GLO Luminescent (Promega, Madison, Wis.) cell culture agentis added to each well for 10 minutes at room temperature to stabilizethe luminescent signal. This determines the number of viable cells inculture based on quantitation of the ATP present, which signals thepresence of metabolically active cells. Luminescence is measured withthe Top Count 384 (Packard Bioscience through Perkin Elmer, Boston,Mass.). Compound inhibition is determined relative to cells culturedwith no drug and the IC₅₀ reported as the compound concentrationrequired for 50% cell death.

IC₅₀ data for the compounds of the Examples as determined by Assay B1 ispresented in Table 2.

TABLE 2 Example No. KMS cellular IC₅₀ (nM)* 1 + 2 + 3 + 4 + 5 + 6 + 7 +8 + 9 ++ 10 ++ 11 + 12 + 13 NA *Symbols used: +: IC₅₀ ≦ 1000 nM ++: 1000nM < IC₅₀ ≦ 10000 nM NA: Not available

Example Assay C1 KMS.12.BM C-Myc ELISA Assay

KMS.12.BM cell line (human myeloma) was purchased from JCRB (Osaka,Japan) and maintained in RPMI with 10% FBS culture medium. To measurethe C-myc inhibitory activity of the compounds, the KMS.12.BM cells areplated in the RPMI culture medium at 75000 cells/well/per 200 μL into a96-well flat bottom polystyrene tissue culture plate (Corning throughVWR, NJ), in the presence or absence of a concentration range of testcompounds. After 2 hours, cell are pelleted and lysed with CellExtraction Buffer (BioSource, Carlsbad, Calif.) in the presence ofprotease inhibitors (Lifetechnologies, Grand Island, N.Y. and Sigma, StLouis, Mo.). Clarified lyses are tested in a C-myc commercial ELISA(Lifetechnologies, Grand Island, N.Y.). Compound inhibition isdetermined relative to cells cultured with no drug and the IC₅₀ reportedas the compound concentration required for 50% C-myc inhibition

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

represents a single bond or a double bond; L is O; X is N or NR⁵; Y isN, CR⁶, C(═O), or C(═S); provided X is not NR⁵ when Y is N; Cy¹ isselected from phenyl and a 5-6 membered heteroaryl group comprisingcarbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, whereinsaid phenyl and 5-6 membered heteroaryl of Cy¹ are optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R¹¹;R¹ and R² are independently selected from H, halo, CN, OH, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a1), SR^(a1),C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1),OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)NR^(c1)R^(d1), NR^(c1)C(═O)OR^(a1), S(═O)R^(b1),S(═O)NR^(c1)R^(d1), S(═O)₂R^(b1), NR^(c1)S(═O)₂R^(b1) andS(═O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹ and R² are optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a1), SR^(a1), C(═O)R^(b1),C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1), NR^(c1)C(═O)NR^(c1)R^(d1),NR^(c1)C(═O)OR^(a1), S(═O)R^(b1), S(═O)NR^(c1)R^(d1), S(═O)₂R^(b1),NR^(c1)S(═O)₂R^(b1) and S(═O)₂NR^(c1)R^(d1); provided R¹ and R² areother than Cl, Br, I, CN, and OH when L is O; alternatively, R¹ and R²together with the carbon atom to which they are attached form a C₃₋₇cycloalkyl group, wherein said cycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R²⁰;Cy³ is selected from phenyl, C₃₋₇ cycloalkyl, a 5-10 membered heteroarylgroup comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, Oand S, and a 4-10 membered heterocycloalkyl group comprising carbon and1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl,C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of Cy³ are optionally substituted with 1, 2, 3, or 4groups independently selected from R¹³, wherein a ring-forming nitrogenatom of said 5-10 membered heteroaryl group or a ring-forming nitrogenatom of said 4-10 membered heterocycloalkyl group is optionallyoxidized; R⁴ is H or C₁₋₆ alkyl; R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₇ cycloalkyl, a 5-6membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatomsselected from N, O and S, and a 4-7 membered heterocycloalkyl groupcomprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S,wherein said C₁₋₆ alkyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl of R⁵ are optionallysubstituted by 1, 2, 3, or 4 groups independently selected from R¹⁵; R⁶is selected from H, halo, CN, OH, OR^(a6), SR^(a6), C(═O)R^(b6),C(═O)NR^(c6)R^(d6), C(═O)OR^(a6), OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(═O)R^(b6), NR^(c6)R^(d6), NR^(c6)C(═O)OR^(a6),S(═O)R^(b6), S(═O)NR^(c6)R^(d6), S(═O)₂R^(b6), NR^(c6)S(═O)₂R^(b6),S(═O)₂NR^(c6)R^(d6), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl of R⁶ areeach optionally substituted by 1, 2, 3, or 4 groups independentlyselected from R¹⁶; alternatively, R⁶ is selected from C₆₋₁₀ aryl, C₃₋₇cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2,3 or 4 heteroatoms selected from N, O and S, and a 4-7 memberedheterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatomsselected from N, O and S, wherein said C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10membered heteroaryl, and 4-7 membered heterocycloalkyl of R⁶ are eachoptionally substituted by 1, 2, 3, or 4 groups independently selectedfrom R²⁰; R⁷ is selected from H, halo, CN, OR^(a), NR^(c)R^(d), SR^(b),CONR^(c)R^(d), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl group comprising carbonand 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7membered heterocycloalkyl group comprising carbon and 1, 2, or 3heteroatoms selected from N, O and S, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroarylgroup, and 4-7 membered heterocycloalkyl group of R⁷ are optionallysubstituted with 1, 2, or 3 groups independently selected from R¹⁷; R⁸is selected from H, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), and CONR^(c)R^(d),wherein said C₁₋₃ alkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl of R⁸ areoptionally substituted with 1, 2, or 3 groups independently selectedfrom R¹⁸; R¹¹ is independently at each occurrence selected from H, C₁₋₃alkyl, C₁₋₃ haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), andCONR^(c)R^(d); R¹³ is independently at each occurrence selected from H,halo, CN, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a3), SR^(a3), C(═O)R^(b3), C(═O)NR^(c3)R^(d3), C(═O)OR^(a3),OC(═O)R^(b3), OC(═O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3),NR^(c3)C(═O)NR^(c3)R^(d3), NR^(c3)C(═O)OR^(a3), S(═O)R^(b3),S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3), NR^(c3)S(═O)₂R^(b3) andS(═O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹³ are optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a3), SR^(a3), C(═O)R^(b3),C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3), OC(═O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3), NR^(c3)C(═O)NR^(c3)R^(d3),NR^(c3)C(═O)OR^(a3), S(═O)R^(b3), S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3),NR^(c3)S(═O)₂R^(b3) and S(═O)₂NR³R^(d3); R¹⁵ is independently at eachoccurrence selected from H, halo, CN, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), C(═O)R^(b5),C(═O)NR^(c5)R^(c5), C(═O)OR^(a5), OC(═O)R^(b5), OC(═O)NR^(c5)R^(c5),NR^(c5)R^(c5), NR^(c5)C(═O)R^(b5), NR^(c5)C(═O)NR^(c5)R^(c5),NR^(c5)C(═O)OR^(a5), S(═O)R^(b5), S(═O)NR^(c5)R^(c5), S(═O)₂R^(b5),NR^(c5)S(═O)₂R^(b5) and S(═O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R¹⁵ are optionally substituted with 1,2, or 3 groups independently selected from halo, CN, OH, OR^(a5),SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(c5), C(═O)OR^(a5), OC(═O)R^(b5),OC(═O)NR^(c5)R^(c5), NR^(c5)R^(c5), NR^(c5)C(═O)R^(b5),NR^(c5)C(═O)NR^(c5)R^(c5), NR^(c5)C(═O)OR^(a5), S(═O)R^(b5),S(═O)NR^(c5)R^(c5), S(═O)₂R^(b5), NR^(c5)S(═O)₂R^(b5) andS(═O)₂NR^(c5)R^(d5); R¹⁶ is independently at each occurrence selectedfrom halo, CN, OH, OR^(a6), SR^(a6), C(═O)R^(b6), C(═O)NR^(c6)R^(d6),C(═O)OR^(a6), OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(═O)R^(b6), NR^(c6)C(═O)NR^(c6)R^(d6), NR^(c6)C(═O)OR^(a6),S(═O)R^(b6), S(═O)NR^(c6)R^(d6), S(═O)₂R^(b6), NR^(c6)S(═O)₂R^(b6),S(═O)₂NR^(c6)R^(d6), C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, a 5-10 memberedheteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl group comprisingcarbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein saidC₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-7 memberedheterocycloalkyl of R¹⁶ are each optionally substituted by 1, 2, 3, or 4groups independently selected R²⁰; R¹⁷ and R¹⁸ are independently at eachoccurrence selected from halo, CN, OR^(a), NR^(c)R^(d), SR^(b), andCONR^(c)R^(d); R^(a), R^(c), and R^(d) are independently at eachoccurrence selected from H and C₁₋₆ alkyl; R^(b) is at each occurrenceC₁₋₆ alkyl; R^(a1), R^(b1), R^(c1) and a R^(d1) are independently ateach occurrence selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl forming R^(a1), R^(b1), R^(c1) and R^(d1) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰; R^(a3), R^(b3), R^(a1) and R^(d3) are independently at eachoccurrence selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a3), R^(b3), R^(a1) and R^(d3) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, OR′, SR′, C(═O)R^(b4), C(═O)NR¹¹R¹¹, C(═O)OR^(a4),OC(═O)R^(b4), OC(═O)NR¹¹R¹¹, NR¹¹R¹¹, NR¹¹C(═O)R^(b4), NR¹¹C(═O)NR¹¹R¹¹,NR¹¹C(═O)OR^(a4), S(═O)R^(b4), S(═O)NR^(c4)R^(d4), S(═O)₂R^(b4),NR^(c4)S(═O)₂R^(b4) and S(═O)₂NR^(c4)R^(d4); R^(a4), R^(b4), R^(c4) andR^(d4) are independently at each occurrence selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl forming R^(a4), R^(b4), R^(c4) and R^(d4)are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R²⁰; R^(a5), R^(b5), R^(c5) and R^(d5) areindependently at each occurrence selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl forming R^(a5), R^(b5), R^(c5) and R^(d5) areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from R²⁰; R^(a6), R^(c6) and R^(d6) are independently at eachoccurrence selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl groupcomprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S,and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or3 heteroatoms selected from N, O and S, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10membered heteroaryl group, and 4-7 membered heterocycloalkyl groupforming R^(a6), R^(c6) and R^(d6) are each optionally substituted with1, 2, or 3 substituents independently selected from R²⁰; alternatively,R^(c6) and R^(d6) together with the nitrogen atom to which they areattached may be combined to form a 4-7 membered heterocycloalkyl groupcomprising carbon, nitrogen, and 0, 1, or 2 additional heteroatomsselected from N, O and S, wherein said 4-7 membered heterocycloalkylgroup is optionally substituted with 1, 2, or 3 substituentsindependently selected from R²⁰; R^(b6) is independently at eachoccurrence selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, phenyl, C₃₋₇ cycloalkyl, a 5-6 membered heteroaryl groupcomprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S,and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or3 heteroatoms selected from N, O and S, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl group, and 4-7 membered heterocycloalkyl group areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from R²⁰; and R²⁰ is at each occurrence independently selectedfrom H, halo, OH, CN, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio,C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ halo alkyl, C₁₋₄ haloalkoxy,C₁₋₄ alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)O—, C₁₋₄ alkyl-OC(═O)—, HOC(═O)—,H2NC(═O)—, C₁₋₄ alkyl-NHC(═O)—, di(C₁₋₄ alkyl)NC(═O)—, C₁₋₄alkyl-C(═O)NH—, C₁₋₄ alkyl-S(═O)—, H₂NS(═O)—, C₁₋₄ alkyl-NHS(═O)—,di(C₁₋₄ alkyl)NS(═O)—, C₁₋₄ alkyl-S(═O)₂—, C₁₋₄ alkyl-S(═O)₂NH—,H₂NS(═O)₂—, C₁₋₄ alkyl-NHS(═O)₂—, and di(C₁₋₄ alkyl)NS(═O)₂—.
 2. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein X is N.
 3. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein X is NR⁵.
 4. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein Y is CR⁶.
 5. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Y is C(═O).
 6. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein X

Y is N═N.
 7. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein Cy¹ is isoxazolyl substituted with 1 or 2 groupsindependently selected from R¹¹.
 8. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy¹ is pyrazolylsubstituted with 1 or 2 groups independently selected from R¹¹.
 9. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from H, methyl, —C(═O)OCH₂CH₃, —C(═O)N(H)CH₂CH₃,—C(═O)N(H)CH₂CH₂OH, and —C(═O)N(CH₃)₂.
 10. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is H.
 11. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is methyl.
 12. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² is H.
 13. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein Cy³ is selectedfrom phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl,dihydrobenzofuranyl and tetrahydrofuranyl, wherein said phenyl,pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyland tetrahydrofuranyl is optionally substituted with 1, 2, 3, or 4groups independently selected from R¹³.
 14. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein Cy³ is phenyloptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R¹³.
 15. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein Cy³ is pyridinyl optionally substituted with 1, 2,3, or 4 groups independently selected from R¹³.
 16. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Cy³ isoxidopyridinyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R¹³.
 17. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy³ is thiazolyloptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R¹³.
 18. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein Cy³ is cyclohexyl optionally substituted with 1,2, 3, or 4 groups independently selected from R¹³.
 19. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Cy³ isdihydrobenzofuranyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R¹³.
 20. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy³ istetrahydrofuranyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R¹³.
 21. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁵ is methyl.
 22. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁵ is H.
 23. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁶ is H, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, or C₁₋₆ haloalkyl.
 24. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R⁶ is H.
 25. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁶ is methoxy.
 26. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁷ is selected from H,halo, C₁₋₄ alkyl, and CN.
 27. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁷ is selected from H,Br, F, methyl, and CN.
 28. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁷ is H.
 29. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁷ is Br.
 30. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ is F.
 31. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R⁷ is methyl. 32.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁷ is CN.
 33. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is selected from H, halo, C₁₋₄alkyl, and CN.
 34. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is H.
 35. The compound of claim 1having Formula (IIa), (IIb), or (IIc):

or a pharmaceutically acceptable salt thereof.
 36. The compound of claim1, having Formula (IIIa), (IIIb), or (IIIc):

or a pharmaceutically acceptable salt thereof.
 37. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein: L is O; Y isN, CR⁶, or C(═O); Cy¹ is a 5-6 membered heteroaryl group comprisingcarbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, whereinsaid 5-6 membered heteroaryl of Cy¹ is optionally substituted with 1, 2,3, or 4 groups independently selected from R¹¹; R¹ is selected from H,F, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R¹ is optionally substituted with 1,2, or 3 groups independently selected from halo, CN, OH, OR^(a1),C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), NR^(c1)R^(d1), andNR^(c1)C(═O)R^(b1); provided R¹ is not OH; R⁷ is selected from H, halo,CN, OR^(a), C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatomsselected from N, O and S, and a 4-7 membered heterocycloalkyl groupcomprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S,wherein said C₁₋₆ alkyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl group, and 4-7 membered heterocycloalkyl group of R⁷ areoptionally substituted with 1, 2, or 3 groups independently selectedfrom R¹⁷; R⁸ is selected from H and C₁₋₃ alkyl; and R^(a1), R^(b1),R^(c1) and R^(d1) are independently at each occurrence selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl.
 38. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: L is O; Y is N, CR⁶,or C(═O); Cy¹ is a 5-membered heteroaryl group comprising carbon and 1,2, 3 or 4 heteroatoms selected from N, O and S, wherein said 5-memberedheteroaryl of Cy¹ is optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R¹¹; R¹ and R² are both H; Cy³ is selectedfrom phenyl and a 5-6 membered heteroaryl group comprising carbon and 1,2, 3 or 4 heteroatoms selected from N, O and S, wherein said phenyl and5-6 membered heteroaryl of Cy³ are optionally substituted with 1, 2, 3,or 4 groups independently selected from R¹³, wherein a ring-formingnitrogen atom of said 5-6 membered heteroaryl group; R⁴ is H; R⁵ isselected from H and C₁₋₆ alkyl; R⁶ is selected from H, OR^(a6); R⁷ isselected from H and halo; and R⁸ is H.
 39. The compound of claim 1selected from:9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one;9-(3,5-dimethylisoxazol-4-yl)-5-methyl-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one;9-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole;9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole;9-(3,5-dimethylisoxazol-4-yl)-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one;9-(3,5-dimethylisoxazol-4-yl)-5-methyl-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one;9-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole;9-(3,5-dimethylisoxazol-4-yl)-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole;7-bromo-9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole;9-(3,5-dimethylisoxazol-4-yl)-3-pyridin-3-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one;9-(3,5-dimethylisoxazol-4-yl)-5-methyl-3-pyridin-3-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one;9-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-pyridin-3-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole;and7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydro[1,2,3]triazolo[1,5,4-de][1,4]benzoxazine;or a pharmaceutically acceptable salt of any of the aforementioned. 40.A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 41. A method of treating cancercomprising administering to a patient in need of such treatment atherapeutically effective amount of a compound of claim 1, wherein thecancer is adenocarcinoma, adult T-cell leukemia/lymphoma, bladdercancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma,myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer,gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladdercancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma,non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngealcancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lungcancer, non-small cell lung cancer, mesothelioma, multiple myeloma,ocular cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitarytumor, primary central nervous system lymphoma, prostate cancer,pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectalcancer, sarcoma, skin cancer, spinal tumor, small intestine cancer,stomach cancer, T-cell lymphoma, testicular cancer, thyroid cancer,throat cancer, urogenital cancer, urothelial carcinoma, uterine cancer,vaginal cancer, or Wilms' tumor.
 42. A method of treating an autoimmuneor inflammatory disease comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of claim 1, whereinthe autoimmune or inflammatory disease is selected from allergy,allergic rhinitis, arthritis, asthma, chronic obstructive pulmonarydisease, degenerative joint disease, dermatitis, organ rejection,eczema, hepatitis, inflammatory bowel disease, multiple sclerosis,myasthenia gravis, psoriasis, sepsis, sepsis syndrome, septic shock,systemic lupus erythematosus, tissue graft rejection, type I diabetes.43. A method of treating a viral infection comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound of claim 1, or a pharmaceutically acceptable salt thereof.44. The method of claim 43, wherein the viral infection is infectionwith adenovirus, Epstein-Barr virus, hepatitis B virus, hepatitis Cvirus, a herpes virus, human immunodeficiency virus, human papillomavirus or a pox virus.